@article {pmid41606687,
year = {2026},
author = {Wang, Y and Mohammadi, B and Hartmann, C and Hartmann, K and Thies, E and Matamoros-Angles, A and Fang, C and Harris, DA and Tatzelt, J and Altmeppen, HC and Sepulveda-Falla, D and Strittmatter, SM and Glatzel, M and Krasemann, S},
title = {Presymptomatic pharmacological inhibition of mGluR5 improves survival in a mouse model of prion diseases.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {41606687},
issn = {2051-5960},
support = {P30 AG066508/AG/NIA NIH HHS/United States ; R01 AG034924/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Toxic signaling of oligomeric protein species via binding to the cellular prion protein (PrP[C]) is implicated in various neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s disease (PD). Metabotropic glutamate receptor 5 (mGluR5) has been identified as a PrP[C] signaling partner, and pharmacological inhibition of mGluR5 was shown to improve cognitive performance and rescue long-term-potentiation (LTP) impairment in both in vitro and in vivo models of AD and PD. Prion diseases are another group of fatal neurodegenerative disorders that are characterized by templated misfolding of endogenous PrP[C] itself into the disease-driving counterpart PrP[Sc]. Besides its role in the self-propagating misfolding cascade and aggregation, PrP[Sc] also acts as a toxic PrP[C] ligand in aberrant signaling through mGluR5. Therefore, targeting metabotropic glutamate receptors has been proposed as a therapeutic strategy for the intervention of prion disease. In this study, we investigated the impact of long-term oral administration of two different selective mGluR5 inhibitors, the negative allosteric inhibitor CTEP and a Silent Allosteric mGluR5 Modulator (SAM), in a mouse model of prion disease. Our findings demonstrate that treatment initiated during the preclinical phase significantly prolonged the survival of mice, whereas treatment starting after the onset of symptoms was no longer effective. Early treatment also delayed the formation of spongiosis, a pathological hallmark of prion diseases, but did not alter PrP[Res] levels. Preclinical dysregulation of mGluR5 could be shown in the mouse and a non-human primate model for prion diseases. Interestingly, in primary neurons, subacute treatment with CTEP blocked Aβ-induced, but not PrP[Sc]-associated synaptotoxicity. Thus, modes of action might differ markedly from those observed in models of Alzheimer’s disease. Together, although our data show that targeting mGluR5 may be an efficient therapy, however, since treatment needs to be started early during prion disease progression, the narrow therapeutic window limits its therapeutic application in human prion diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-026-02235-9.},
}

@article {pmid41772032,
year = {2026},
author = {Zolfaghari, S and Gholizadeh, E and Garehdaghi, F},
title = {Integrating attractor dynamics and connectivity features for EEG-based dementia classification.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41772032},
issn = {2045-2322},
abstract = {The precise differentiation between Alzheimer’s disease (AD) and frontotemporal dementia (FTD) presents a clinical challenge, as both conditions share overlapping symptoms yet diverge in their pathophysiological mechanisms and treatment strategies. Electroencephalography (EEG), characterized by its higher temporal resolution and widespread applicability, provides the opportunity to uncover subtle discrepancies in brain dynamics that may be difficult to detect with conventional neuroimaging techniques. This paper presents a system that combines nonlinear attractor-based features derived from phase-space representations with phase-locking value connectivity features to encapsulate both local and global brain dynamics. In this regard, resting-state EEG recordings from 36 AD patients, 23 FTD patients, and 29 healthy controls (HC) were preprocessed and analyzed to extract dynamic and network features. Multiple classifiers were then used to assess these features under stratified 10-fold cross-validation. The results showed that the support vector machine achieved the highest performance for AD vs. FTD (81.7%), logistic regression performed well for FTD vs. HC (81.0%), and gradient boosting reached 82.9% for AD vs. HC. These findings illustrate the capability of EEG as a low-cost diagnostic technique, suggest that attractor dynamics and connectivity can offer complementary perspectives on the brain alterations linked to dementia, and enhance classification performance.},
}

@article {pmid41772634,
year = {2026},
author = {Das, RK and Sahoo, N and Roy, D and Nguyen, L and Rodrigo, H and Duttaroy, AK and Fields, JA and Roy, U},
title = {Interferon-induced protein IFIT3 as a molecular nexus of neuroinflammation in Alzheimer's disease and HIV-associated neurocognitive disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41772634},
issn = {1742-2094},
support = {SC2GM139715//UTRGV internal funding/ ; R15NS108815 and R01AI147731//National Institute of Health, USA/ ; P30AG059305//NASA-MUREP, NASA-MOSAIC, UTRGV-Resource Centers for Minority Aging Research (RCMAR)/ ; U54MD019970//NIMHD grant/ ; },
abstract = {UNLABELLED: Alzheimer’s disease (AD) and HIV-associated neurocognitive disorder (HAND) are significant global health concerns characterized by cognitive impairment and shared pathological features, including chronic neuroinflammation, amyloid deposition, and immune dysregulation. However, the precise molecular connections between these disorders remain unclear. Here, we identify IFIT3 as a critical shared mediator of neuroinflammatory responses in both AD and HAND. Using complementary approaches, including neuronal and microglial cell cultures, the APP/PS1 mouse model, and human postmortem brain tissues, we demonstrate consistent IFIT3 upregulation in response to amyloid-beta (Aβ) and HIV-1 exposure, with notably enhanced expression under combined conditions. Treatment with combination antiretroviral therapy (cART) partially mitigated IFIT3 induction. Additionally, siRNA-mediated silencing of IFIT3 significantly reduced key inflammatory mediators, including mitochondrial antiviral signaling protein (MAVS), nuclear factor-κB, and proinflammatory cytokines. Clinically, elevated IFIT3 expression was associated with early HAND and progressively increased across advancing AD Braak stages. Together, these findings identify IFIT3 as a potential molecular bridge between HAND and AD, highlighting its promise as both a biomarker and a therapeutic target for inflammation-driven neurodegeneration.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03713-6.},
}

@article {pmid41776457,
year = {2026},
author = {Tang, Y and Yang, R and Zhang, M and Zhou, C and Chen, M and Pan, H and Qin, Y and Gui, Y and Fan, G},
title = {Classifying drug-related problems of neurodegenerative diseases in the physician-pharmacist joint clinic of neurology: an application of the PCNE method.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {41776457},
issn = {1471-2318},
support = {22QA1411400//Shanghai Science and Technology Development Funds/ ; 81973289//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: The prevalence of neurodegenerative diseases (NDDs) is escalating, and complex medication regimens lead to a high incidence of drug-related problems (DRPs). This study analyzes DRPs in this population to identify their incidence and causes. The findings aim to provide a theoretical basis for clinical intervention strategies and outpatient pharmacy monitoring, ultimately ensuring rational drug use and enhancing patient safety.

METHOD: This study was conducted among patients with neurodegenerative diseases at a major hospital in Shanghai, China, between July 2023 and June 2024. The Pharmaceutical Care Network Europe (PCNE) classification system version 9.1 was used to identify DRPs. Data was entered and analyzed using SPSS software. Full model and stepwise logistic regression analyses were used to identify predictors of DRP occurrence in the total sample and Alzheimer’s disease (AD)/Parkinson’s disease (PD) subgroups. Outpatient medications were summarized. A p-value of less than 0.05 was considered statistically significant.

RESULT: A total of 254 patients (90 AD, 171 PD) were involved, resulting in 398 DRPs. The most commonly encountered type of DRP was treatment effectiveness (48.99%), and drug selection (46.73%) was the most common cause. The majority of clinical pharmacist interventions were provided at the drug level (98.99%), primarily involving dose adjustment and usage method adjustment. The acceptance level of interventions by prescribers was high (90.70%), with the acceptance rate in AD patients (92.96%) being higher than that in PD patients (90.07%). Through pharmacist intervention, over 70% of DRPs were completely resolved. Anti-Parkinson’s disease drugs, antianxiety or antidepressant drugs, and sedatives and hypnotics were the three main drug classes contributing to DRPs. Lifestyle habits (smoking, drinking), the number of comorbidities, and the dose of medication were factors associated with the development of DRPs.

CONCLUSION: This study finding revealed that DRPs were prevalent in patients with PD and AD. Medication care was a protective factor, whereas polypharmacy and the presence of multiple comorbidities were significantly associated with an elevated risk of DRPs. Based on the PCNE classification and the “PCIAO” process, clinical pharmacists’ involvement in precision management offers a robust evidence base and provides clear guidance for optimizing therapeutic regimens.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-026-07234-y.},
}

@article {pmid41776637,
year = {2026},
author = {Wang, L and Wang, F and Wang, X and Chen, X and Li, C and Shan, K and Zhou, H and Wu, G and Xu, Z and Kong, X and Wei, P},
title = {The lung-brain axis: elucidating the mechanisms of pulmonary-driven neurological disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41776637},
issn = {1742-2094},
support = {22201164//National Natural Science Foundation of China/ ; 82571352//National Natural Science Foundation of China/ ; QDZDZK-2025064//the Qingdao Key Health Discipline Development Fund/ ; ZR2024QH041//the Natural Science Foundation of Shandong Province/ ; QDKY2023ZD02//the Scientific Research Foundation of Qilu Hospital of Shandong University/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {The brain and lungs represent two of the most vital organs in the human body. The conceptualization of the lung-brain axis has advanced our understanding of the bidirectional communication between the respiratory and central nervous systems. Accumulating evidence indicates that pulmonary diseases, including chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and infections such as bacterial pneumonia, influenza and Coronavirus Disease 2019, along with airborne environmental exposures, constitute significant risk factors for various neurological disorders. The lung-brain axis is primarily mediated by microbial, immune, neural, metabolic and hormonal pathways. These mechanisms contribute to the disruption of blood-brain barrier integrity, the activation of neuroglial cells and the dysfunction of the cerebrovascular system, ultimately causing neuronal injury and diverse neurological conditions. Environmental factors, notably airborne particulate matter and chemical pollutants, further amplify the crosstalk among these mechanisms, extending the neurological risk. Here, we summarize the current knowledge regarding the association between pulmonary dysfunction and the development and progression of neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), stroke, anxiety/depression, epilepsy, and migraine. Additionally, potential therapeutic strategies targeting the lung–brain axis are discussed to foster further research in this emerging field. Elucidating the complex interactions within the lung–brain axis will not only deepen our understanding of the shared pathophysiological mechanisms but also open novel avenues for the early diagnosis, prevention, and treatment of related neurological diseases.},
}

@article {pmid41776683,
year = {2026},
author = {Shin, H and Lee, S and Seo, W and Yoon, SH and Cho, I and Ye, S and Park, I and Yoon, S and Park, M and Kim, S and Lee, S and Kim, HY and Kim, I and Kim, Y},
title = {YIAD-0501 directly dissociates aggregates of full-length and N-terminal pyroglutamate-modified forms of Aβ.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41776683},
issn = {1758-9193},
support = {RS-2018-NR031048//Basic Science Research Program, National Research Foundation of Korea (NRF), Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2025-00523607//Mid-Career Researcher Program, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2021-NR059653//Mid-Career Researcher Program, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00349158//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00418203//Korea Institute for Advancement of Technology/ ; },
abstract = {BACKGROUND: Recent approvals of amyloid-β (Aβ) antibody drugs have established amyloid clearance as a viable therapeutic approach in Alzheimer’s disease (AD). However, despite substantial amyloid reduction, their cognitive benefits remain modest, potentially reflecting incomplete targeting of the structurally diverse pathogenic Aβ assemblies that drive AD progression. Given this molecular heterogeneity, a therapeutic strategy capable of targeting multiple toxic Aβ forms is required to achieve broader efficacy. To address this need, we investigated YIAD-0501, a small-molecule candidate designed to simultaneously engage multiple pathogenic Aβ species, including oligomeric and fibrillar forms of Aβ (1–42) and pyroglutamate Aβ(pE3–42).

METHODS: A series of 6H-furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine derivatives was synthesized and screened by Thioflavin T fluorescence and A11 dot blot assays to identify compounds active against diverse pathogenic Aβ assemblies. The lead compound, YIAD-0501, was further characterized by transmission electron microscopy, circular dichroism, microscale thermophoresis, molecular docking, and amyloid plate mapping to define its Aβ interaction and structural effects. For in vivo evaluation, YIAD-0501 (10 mg/kg, daily for 4 weeks) was administered to 6-month-old male 5XFAD mice, followed by Y-maze testing for spatial working memory and contextual fear conditioning for hippocampal-dependent memory. Biochemical analyses, including immunoblotting, immunohistochemistry, and ELISA, were subsequently conducted to quantify Aβ plaque burden, soluble Aβ levels, and gliosis.

RESULTS: YIAD-0501 effectively reduced both oligomeric and fibrillar assemblies of Aβ (1–42) and Aβ(pE3–42) in vitro. Molecular docking and amyloid mapping analyses indicated interactions between YIAD-0501 and both the C-terminal hydrophobic region and the KLVFFA aggregation core of Aβ, consistent with the observed reduction in β-sheet content and direct binding. In 5XFAD mice, YIAD-0501 treatment decreased amyloid plaque burden, soluble Aβ levels, and neuroinflammation in the hippocampus, accompanied by improvements in spatial working and hippocampal-dependent memory.

CONCLUSIONS: Collectively, our findings identify YIAD-0501 as a small-molecule candidate that reduces multiple pathogenic Aβ assemblies and ameliorates hippocampal pathology and memory deficits in the 5XFAD mouse model. These findings highlight a chemically driven, multi-target mode of Aβ clearance, representing a strategy for broader intervention across the heterogeneous pathogenic landscape of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01999-5.},
}

@article {pmid41862973,
year = {2026},
author = {Marei, HE},
title = {Enhancer-based gene therapy: a new path for precision medicine.},
journal = {Hereditas},
volume = {163},
number = {},
pages = {},
pmid = {41862973},
issn = {1601-5223},
abstract = {Enhancers are critical cis-regulatory elements that regulate gene expression in a context-dependent manner by integrating transcription factor binding, chromatin state, and the three-dimensional organization of the genome. Recent advances in functional genomics and synthetic biology have increased interest in harnessing enhancer activity to regulate the expression of therapeutic genes. Unlike traditional approaches that rely on promoter-driven gene regulation, enhancer-based approaches can bias transgene expression toward specific cellular states or disease contexts; however, this control remains probabilistic and highly dependent on the chromatin environment. This review summarizes current knowledge of enhancer biology, discusses new strategies for utilizing enhancer function directly, and examines the potential benefits and drawbacks of using enhancer-based strategies for gene therapy applications. Often delivered using adeno-associated virus (AAV) vectors with tailored capsids, enhancers in gene therapy can be included into expression cassettes. Astrocyte- or microglia-specific enhancers in the brain enable enriched or preferential distribution of neuroprotective or immunomodulatory genes, hence lowering unintentional expression in non-target cell types. It is important to control gene expression for specific cell types for the treatment of neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease, were unintentional gene expression results in negative consequences. However, the uses of enhancer-guided gene therapy go beyond the central nervous system. In cancer, therapeutic constructs are designed to inhibit oncogenic expression or induce tumor suppression pathways, using enhancers in either malignant or immune cells as a target. Similarly, through the use of tissue-specific enhancers in cardiovascular and regenerative medicine, lineage-enriched genes can be used to promote repair of damaged tissues and enhance functional recovery. Enhancer-based systems that modulate the levels of gene expression (enhancer systems that adjust gene expression to levels that are physiologically appropriate for a given cell type) may also be useful in diseases caused by imbalances of gene dosage (e.g., haploinsufficiency and copy number variations). However, despite the potential promise of enhancer-driven gene therapy, many technical and translational hurdles remain. Mapping and validating the function of cell-type-specific enhancers is hampered by the dynamic, context-dependent regulation of chromatin. The identification of enhancers across a variety of developmental stages and clinical states is being accelerated through the combination of recent advances in single-cell epigenomic techniques (e.g., ATAC-seq, ChIP-seq, and multi-omic integration). Recent advances in non-viral delivery methods and AAV capsid engineering are improving the safety, efficacy, and scalability of enhancer-driven gene therapies. However, there must be careful regulatory oversight to avoid unintentional activation of enhancers and ensure continuing efficacy of enhancer-guided therapies. This paper provides an overview of the conceptual basis of enhancer-driven gene therapies, the currently available applications, and barriers to their clinical application. We show how the combination of delivery technology, synthetic biology, and genomics is enabling new possibilities for tailored gene therapy particular to cell- and disease-specific. Enhancer-driven gene therapy could become an important component of next-generation precision medicine by addressing current challenges and using creative technology.},
}

@article {pmid41865008,
year = {2026},
author = {Borgström Bolmsjö, B and Barbosa Djärf, J and van Westen, D and Schindler, SE and Fawad, A and Collij, L and Smith, R and Mattsson-Carlgren, N and Stomrud, E and Tideman, P and Hansson, O and Palmqvist, S},
title = {Eligibility for amyloid targeting therapies among primary care patients with cognitive symptoms.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {},
pages = {},
pmid = {41865008},
issn = {1758-9193},
abstract = {BACKGROUND: Alzheimer’s disease (AD) is the most common cause of dementia and a growing healthcare challenge. Amyloid-targeting therapies (ATT) may slow progression, but implementation is limited by logistical and economic barriers. As primary care is the first contact for most patients with cognitive concerns, quantifying treatment eligibility in this setting is essential. The purpose of this study was to estimate the proportion of primary care patients presenting with cognitive symptoms who are eligible for ATT.

METHODS: This cohort study included patients presenting with cognitive symptoms in primary care across the region Skåne, in southern Sweden, recruited between January 2020 and April 2025. Stepwise exclusion criteria based on clinical diagnosis, comorbidities, and treatment contraindications were applied, in alignment with appropriate use recommendations for lecanemab and donanemab, respectively. Eligibility was further refined using CSF biomarkers (Aβ42/40 ratio), cognitive performance, and MRI findings.

RESULTS: In a full diagnostic work-up of 607 patients with sequential exclusions, 86 patients (14.2%) and 78 patients (12.8%) ultimately met the eligibility criteria for lecanemab and donanemab, respectively. Due to comorbidities, medication use, and age/BMI, around 1/3 of the original population was excluded. Most ineligible patients met more than one exclusion criterion. The eligible population was 63% female, mean age 77 years. Around 65% of the individuals had mild cognitive impairment (MCI), and 35% mild dementia.

CONCLUSIONS: About 13-14% of primary care patients evaluated for cognitive complaints were eligible for ATT. Compared with clinical trials, the eligible population was older and consisted of more women.

TRIAL REGISTRATION: BioFINDERPrimary Care study (NCT06120361, Registration date 2 November 2023 https//biofinder.se).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02019-2.},
}

@article {pmid41904593,
year = {2026},
author = {Merkel, J and Perneczky, R and Jessen, F and Frölich, L and Jansen, O and Peters, S and Berg, D and Schulz, JB and Bartsch, T},
title = {Amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease: from pathophysiology to individualized risk assessment.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {},
pages = {},
pmid = {41904593},
issn = {1758-9193},
abstract = {UNLABELLED: Monoclonal antibodies targeting amyloid-β are the first approved disease-modifying treatment for Alzheimer’s disease. While amyloid-targeting therapies mitigate the progression of cognitive decline in early-stage Alzheimer’s disease, they are associated with amyloid-related imaging abnormalities (ARIA), an imaging phenomenon presenting as cerebral edema/effusion and/or hemorrhage. Redistribution of parenchymal amyloid-β to perivascular drainage pathways and direct antibody-amyloid interactions within the cerebral vasculature are considered key players in ARIA pathophysiology by promoting inflammation and vascular disruption, thus mirroring hallmarks of inflammatory cerebral amyloid angiopathy. Although ARIA is commonly regarded as an undesired side effect of amyloid-targeting therapies, its association with amyloid-β clearance from the brain opens up the possibility of an alternative interpretation as a physiological reaction to target engagement of anti-amyloid antibodies. Understanding risk factors that promote the occurrence of ARIA and its transformation from asymptomatic imaging phenomenon to its serious and severe form are of great importance to clinical practice. ARIA risk and severity are influenced by apolipoprotein E4 status, microvascular damage, and cerebral amyloid angiopathy, but may be further modulated by antibody binding preferences and comorbidities such as arterial hypertension and ischemic strokes. Identifying individual risk profiles based on deeper insights into pathophysiological pathways may improve patient safety and lead to personalized treatment concepts in Alzheimer’s disease. In this review, we provide a comprehensive summary of ARIA pathophysiology, highlight important risk factors and discuss their relevance in clinical risk management.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02022-7.},
}

@article {pmid41946775,
year = {2026},
author = {Phemphunananchai, K and Waiwut, P and Phetcharaburanin, J and Poonsawas, P and Boonyarat, C},
title = {Repurposing FDA-approved drugs as multi-target neuroprotective agents for Alzheimer's disease via computational screening and experimental validation.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41946775},
issn = {2045-2322},
support = {67-2(7)/2567//Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand/ ; RA2567-M109//The Research Assistant Program, Khon Kaen University, Thailand/ ; },
abstract = {UNLABELLED: β-site APP-cleaving enzyme 1 (BACE1, a β-secretase) is a key aspartyl protease that initiates the proteolytic processing of the amyloid precursor protein (APP) to form the amyloid-β (Aβ) peptide. Given that Aβ aggregation and plaque formation are a central pathological feature of Alzheimer’s disease (AD), BACE1 remains a critical therapeutic target. Furthermore, the complexity of AD pathology necessitates the identification of novel multi-target agents. This study employed a structure-based virtual screening, targeting the BACE1 approach to identify the potential BACE1 inhibitors from FDA-approved drug scaffolds derived from the ZINC database. Top-ranked candidates were subsequently validated through extensive 500 ns molecular dynamics (MD) simulations and in vitro assays of BACE1 inhibition activity. Furthermore, multi-AD-related target profiling of candidates was conducted using molecular docking and a series of in vitro assays. Among them, ZINC000019796155 emerged as a promising multi-target compound. Biochemical analysis revealed that ZINC000019796155 exhibited moderate inhibitory effects against BACE1. Subsequent assays confirmed its capacity to inhibit butyrylcholinesterase (BuChE) action and Aβ aggregation, function as a free radical scavenger, and provide neuroprotection against H2O2-induced oxidative stress in cellular models. Furthermore, western blot analysis elucidated the mechanism of neuroprotection, indicating that ZINC000019796155 inhibits the apoptotic pathway while simultaneously suppressing the formation of Aβ plaques and neurofibrillary tangles (NFTs). These findings highlight ZINC000019796155 as a validated scaffold with a known safety profile for AD. While further structural optimization and preclinical in vivo studies are necessary, this study underscores the potential of ZINC000019796155 as a multi-target neuroprotective agent for AD treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-46708-2.},
}

@article {pmid41950049,
year = {2026},
author = {Robb, WH and Kaur, G and Huang, S and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Conyers, CT and Grilli, CB and Upjohn, DP and Ortega, VE and Hohman, TJ and Keegan, RM and Parent, EE and Cogswell, PM and Graff-Radford, J and Johnson, DR and Ramanan, VK and Koran, ME},
title = {Health system patterns of imaging and fluid biomarker testing in the era of anti-amyloid therapies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71343},
pmid = {41950049},
issn = {1552-5279},
support = {//Alzheimer's Association Clinician Scientist Fellowship (MEK)/ ; K76AG088554/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; Female ; *Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/diagnosis ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors ; Retrospective Studies ; Aged ; Positron-Emission Tomography ; Apolipoproteins E/genetics ; Brain/diagnostic imaging ; Middle Aged ; tau Proteins/cerebrospinal fluid/blood ; Aged, 80 and over ; Electronic Health Records ; },
abstract = {INTRODUCTION: Anti-amyloid-β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real-world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care.

METHODS: Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019-Mar 2025) assessed trends in AD-relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid-beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated.

RESULTS: Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (-25/quarter), and plasma p-tau217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive (p < 0.006). APOE-ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001).

DISCUSSION: The adoption of anti-Aβ therapies coincided with a rapid shift in diagnostic workflows.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
Female
*Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/diagnosis
Male
*Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors
Retrospective Studies
Aged
Positron-Emission Tomography
Apolipoproteins E/genetics
Brain/diagnostic imaging
Middle Aged
tau Proteins/cerebrospinal fluid/blood
Aged, 80 and over
Electronic Health Records

@article {pmid41951598,
year = {2026},
author = {Zhao, S and Ye, R and Tang, QY and Attaallah, B and Toniolo, S and Saleh, Y and Rouse, MA and Garrard, P and Broulidakis, MJ and Thompson, S and Manohar, SG and Irani, SR and Ang, YS and Lockwood, P and Apps, MAJ and Hu, P and Wang, K and Rowe, JB and Le Heron, C and Husain, M},
title = {The social dimension of apathy: evidence for a distinct domain from 11,243 individuals across health and neurocognitive disorders.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04023-4},
pmid = {41951598},
issn = {2158-3188},
support = {226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 82171917//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82471271//National Natural Science Foundation of China (National Science Foundation of China)/ ; MR/V007173/1//RCUK | Medical Research Council (MRC)/ ; MC_UU_00030/14//RCUK | Medical Research Council (MRC)/ ; SUAG/092 G116768//RCUK | Medical Research Council (MRC)/ ; 02/2019//Canterbury Medical Research Foundation (CMRF)/ ; },
abstract = {Apathy is a highly prevalent and disabling neuropsychiatric syndrome, but its multi-dimensional structure is a challenge for progress towards better identification and treatment. A crucial unresolved question is whether social disengagement reflects a distinct deficit in social motivation or a by-product of diminished initiative or emotional blunting. Previous studies have been constrained by modest sample sizes and limited use of apathy-specific instruments or phenotypically narrow cohorts. Here, we analysed item-level data from 11,243 individuals recruited across multiple centres, including 1154 neurological patients with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, autoimmune encephalitis and small vessel disease, alongside people with depression and healthy adults. Across exploratory and confirmatory factor analyses, symptom-level network modelling, and lifespan analyses, social apathy consistently emerged as a coherent and separable dimension. This pattern was preserved across health, psychiatric, and neurocognitive cohorts, from adolescence through late life. Recognising social apathy as an independent domain reframes a central aspect of mental health-the motivation to connect, care, and act for others-and provides a foundation for more precise assessment and for interventions targeting both social and neurobiological mechanisms.},
}

@article {pmid41951832,
year = {2026},
author = {Islam, N and Akçesme, B},
title = {Single nucleotide polymorphisms affecting galantamine binding to acetylcholinesterase in Alzheimer's disease: a structural bioinformatics study.},
journal = {Journal of computer-aided molecular design},
volume = {40},
number = {1},
pages = {},
pmid = {41951832},
issn = {1573-4951},
mesh = {*Galantamine/chemistry/metabolism ; Humans ; *Alzheimer Disease/drug therapy/genetics/enzymology ; *Acetylcholinesterase/chemistry/genetics/metabolism ; *Cholinesterase Inhibitors/chemistry/metabolism/pharmacology ; Molecular Dynamics Simulation ; *Polymorphism, Single Nucleotide ; Molecular Docking Simulation ; Protein Binding ; Computational Biology ; Binding Sites ; Ligands ; Catalytic Domain ; Thermodynamics ; },
abstract = {Galantamine, an acetylcholinesterase (AChE) inhibitor used for symptomatic treatment of Alzheimer's disease (AD), shows substantial inter-individual variability in clinical response. Missense single nucleotide polymorphisms (SNPs) within the AChE active-site gorge may modulate inhibitor recognition. In this computational study, binding residues were defined from human AChE inhibitor co-crystal structures and cross-referenced with dbSNP missense variation, followed by in-silico predictions of variant impact, evolutionary conservation and folding stability, and assessment of ligand engagement by docking and molecular dynamics (MD) with MM/GBSA binding-energy estimation. Using complexes containing galantamine (GNT) and a donepezil-like ligand (E20), 11 of 807 AChE missense variants overlapped binding-site residues, highlighting Phe294 (UniProt Phe326) and His447 (UniProt His479). ConSurf classified His447 as highly conserved, and MUpro predicted decreased folding stability for His447 substitutions. SwissDock docking indicated that His447Gln retains a plausible GNT binding pose and yielded the least favourable docking score among the tested variants, consistent with a potential reduction in binding strength. MD simulations (200 ns) of wild-type and His447Gln AChE-GNT complexes supported preserved global structural integrity of the complex over the simulated timescale, while indicating local remodelling of the GNT binding microenvironment. MM/GBSA estimates from terminal snapshots suggested a modestly less favourable theoretical binding free energy for His447Gln relative to wild-type (approximately 2.0 kcal mol[-1]). Given that His447 is the catalytic triad histidine, such substitutions may have consequences for catalysis in addition to inhibitor binding; these in-silico findings require experimental validation using site-directed mutagenesis with kinetic and binding assays.},
}

*Galantamine/chemistry/metabolism
Humans
*Alzheimer Disease/drug therapy/genetics/enzymology
*Acetylcholinesterase/chemistry/genetics/metabolism
*Cholinesterase Inhibitors/chemistry/metabolism/pharmacology
Molecular Dynamics Simulation
*Polymorphism, Single Nucleotide
Molecular Docking Simulation
Protein Binding
Computational Biology
Binding Sites
Ligands
Catalytic Domain
Thermodynamics

@article {pmid41953054,
year = {2026},
author = {Zhuang, YY and Yan, JM and Wu, TC and Xu, WS and Wu, B and Xie, X and Wang, WJ and Lin, HW and Jian, JW and Wang, JZ and Jiang, T and Chen, LM and Qiu, YX and Hu, ZY and Zhou, YH and Yang, T and Yang, MG and Zhu, JF and Tao, J and Chen, LD and Li, WG and Yan, K and Liu, WL},
title = {tDCS improves early Alzheimer's disease by synaptic vesicle fusion and release.},
journal = {Military Medical Research},
volume = {13},
number = {1},
pages = {100003},
pmid = {41953054},
issn = {2054-9369},
mesh = {*Alzheimer Disease/therapy/physiopathology ; Animals ; Mice ; *Transcranial Direct Current Stimulation/methods/standards ; *Synaptic Vesicles/physiology/metabolism ; Mice, Transgenic ; Prefrontal Cortex/physiopathology ; Disease Models, Animal ; Male ; Memory, Short-Term ; Humans ; },
abstract = {BACKGROUND: Working memory deficits, one of the earliest hallmarks of Alzheimer's disease (AD), are closely linked to abnormal neural activity in the dorsolateral prefrontal cortex (DLPFC). Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation therapy, has been shown to ameliorate early AD working memory deficits by modulating excitatory activity in the DLPFC, yet the underlying mechanisms remain incompletely understood.

METHODS: This investigation was structured around 3 experimental phases. We initially applied tDCS to stimulate the left prefrontal cortex (PFC) of transgenic mice with 5 familial AD (5×FAD) 5 d per week for 4 weeks. Subsequently, we employed optogenetic (Opt) techniques to modulate left PFC glutamatergic neurons. Finally, we inhibited soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) expression in the left PFC to elucidate the essential function of SNARE complex assembly with chaperone molecules in orchestrating synaptic vesicle release.

RESULTS: tDCS treatment improved working memory deficits in early-stage AD mice. This was accompanied by increased cerebral blood flow, enhanced neuronal excitability, amelioration of neurochemical metabolic disorders, and reduced amyloid β-protein (Aβ) deposition in the left PFC. Opt stimulation of PFC glutamatergic neurons similarly improved working memory, indicating the association between tDCS's therapeutic effects and synaptic plasticity of excitatory neurons. Crucially, tDCS facilitated synaptic vesicle fusion and release, evidenced by increased vesicle numbers, enhanced release probability, improved synaptic transmission efficacy, and upregulation of the SNARE complex, Snap25, and Syt1. Inhibiting SNARE expression in the left PFC attenuated the tDCS-induced improvements in synaptic vesicle release and working memory.

CONCLUSION: These findings collectively demonstrate that left PFC-targeted tDCS modulates interactions between the SNARE complex and chaperone molecules, thereby promoting synaptic vesicle fusion and release. This mechanism underlies the amelioration of early AD-like working memory impairment by tDCS.},
}

*Alzheimer Disease/therapy/physiopathology
Animals
Mice
*Transcranial Direct Current Stimulation/methods/standards
*Synaptic Vesicles/physiology/metabolism
Mice, Transgenic
Prefrontal Cortex/physiopathology
Disease Models, Animal
Male
Memory, Short-Term
Humans

@article {pmid41954680,
year = {2026},
author = {Youssef, B and Ibrahim, EA and Moselhy, SS and ElShebiney, S and ELabd, WK},
title = {Nano-magnolol enhances the modulatory effects of magnolol on cognitive performance and BACE1-related biochemical changes in an STZ-induced rat model of Alzheimer's disease.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {41954680},
issn = {2731-9229},
abstract = {BACKGROUND: The Late-onset Alzheimer's disease (LOAD) is progressive cognitive deficits associated with different abnormalities as cholinergic dysfunction, amyloid accumulation, inflammation, and oxidative stress. Magnolol is a polyphenolic compound that abrogated the neurodegenerative disease. The application of nanoparticles in medicine showed high bioavailability and low side effects for development of novel effective therapies. This study evaluated the neuroprotective potential of magnolol nanoparticles against streptozotocin (STZ) injected in intracerebroventricularly (ICV) induced Alzheimer's disease (AD) in rats.

METHODS: In current study, six groups of male Wister rats (10 rats/ group) were injected with STZ (2 mg/kg) in ICV bilaterally for induction of pathological features similar to AD. Rats were then treated with either magnolol or nano-magnolol or donepezil (p.o). Behavioral analysis was evaluated as the Morris Water Maze (MWM), Y-Maze, Novel Object Recognition (NOR), Passive Avoidance (PA), Elevated plus Maze (EPM), and Open Field Test (OFT). In addition, biochemical markers including brain acetylcholinesterase (AChE), glutathione-S-transferase (GST), B-secretase1 (BACE1) activities and nuclear factor kappa-B (NF-κB) were analyzed in hippocampal tissue.

RESULTS: Data obtained showed that nano-magnolol significantly showed a neuroprotective effect in LOAD rat model by restoring GST activity and effectively decreased the activities of AChE, BACE1 and level of NF-κB compared to both donepezil and magnolol. Molecular docking studies indicated strengthen the affinity of magnolol to the BACE-1 active site.

CONCLUSION: Nano-magnolol is promising in developing a new agent targeting cholinergic function, amyloidogenesis, neuro-inflammation, and oxidative stress reflecting its potent neuroprotective efficacy in AD treatment.},
}

@article {pmid41954847,
year = {2026},
author = {Ma, X and Wang, M and Yang, J and Li, G and Wang, Y and Fang, H and Zhang, S},
title = {Integrated Single-Cell and System Network Analysis: Exploring Cellular Communication Network Complexity and Signal Transmission Dysregulation in Down Syndrome Brain.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {41954847},
issn = {1559-0089},
support = {No. 2022D03052; No. XJNUBS202419; Grant Numbers. 82270417//This research was supported by the Special Natural Science Foundation of Xinjiang Uygur Autonomous Region Special Training Programme for Ethnic Minorities (No. 2022D03052), the Doctoral (Postdoctoral) Research Start-up Fund Project of Xinjiang Normal University (No. XJNUBS202419) and the National Natural Science Foundation of China (Grant Numbers. 82270417)./ ; No. 2022D03052; No. XJNUBS202419; Grant Numbers. 82270417//This research was supported by the Special Natural Science Foundation of Xinjiang Uygur Autonomous Region Special Training Programme for Ethnic Minorities (No. 2022D03052), the Doctoral (Postdoctoral) Research Start-up Fund Project of Xinjiang Normal University (No. XJNUBS202419) and the National Natural Science Foundation of China (Grant Numbers. 82270417)./ ; },
mesh = {*Down Syndrome/metabolism/pathology/genetics ; Humans ; *Cell Communication/physiology ; Middle Aged ; Male ; Female ; Adult ; *Brain/metabolism/pathology ; *Single-Cell Analysis/methods ; Neurons/metabolism ; Young Adult ; Signal Transduction/physiology ; Aged ; },
abstract = {Down syndrome (DS) is a widespread chromosomal disorder primarily associated with cognitive impairment and progressive neurodegenerative changes. Clinically, age 50 years is considered a pivotal turning point in the health trajectory of individuals with DS. Before this age, they primarily face developmental challenges including significant cognitive deficits and difficulties in social interaction. However, as they age, they increasingly exhibit more severe neurodegenerative changes, including Alzheimer's disease (AD)-like cognitive decline and dementia symptoms. This study aimed to dissect intricate gene expression patterns in key neuronal cell types within the DS cerebral cortex and to examine how these patterns evolve with age. We conducted a detailed gene expression analysis of key neuronal cells, including inhibitory neurons, excitatory neurons, microglia, and oligodendrocyte progenitor cells, in individuals with DS. Additionally, the bioinformatics tool NeuronChat was employed to investigate the intercellular communication networks in the DS brain. Individuals with DS were divided into younger and older groups, with age 50 years as the boundary. Through comparative analysis, our findings indicated that aging in DS is associated with exacerbated neuronal dysfunction, decreased energy metabolism in microglia, and increased neurodegenerative traits in oligodendrocyte progenitor cells. Notably, compared to the control group, the DS brain showed increased complexity in cellular communication networks, reflecting an effort to maintain adaptability during syndrome progression. However, this increased complexity does not translate into effective signal transmission, suggesting significant disruptions in the function and structure of the neural network. This study provides a deeper understanding of cell function abnormalities and signal transmission irregularities in DS. By integrating single-cell and systemic network analyses, we revealed complex pathophysiological mechanisms, laying a foundational framework for developing new treatment methods. Our comprehensive analysis emphasizes the necessity for targeted strategies to address the multifaceted nature of DS pathogenesis and improve treatment outcomes.},
}

*Down Syndrome/metabolism/pathology/genetics
Humans
*Cell Communication/physiology
Middle Aged
Male
Female
Adult
*Brain/metabolism/pathology
*Single-Cell Analysis/methods
Neurons/metabolism
Young Adult
Signal Transduction/physiology
Aged

@article {pmid41955600,
year = {2026},
author = {Krupa, J and Malinowski, M and Krasowski, M and Kalinowska, A and Pietras, W and Kozieł, A and Kurek, Z and Jentkiewicz, A and Obeid, EH and Ulrych, J},
title = {The role of the MIND diet in prevention and treatment of Alzheimer's disease: A literature review.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {2},
pages = {390-398},
doi = {10.36740/WLek/217286},
pmid = {41955600},
issn = {0043-5147},
mesh = {Humans ; *Alzheimer Disease/prevention & control/diet therapy ; *Diet ; },
abstract = {OBJECTIVE: Aim: Recent research increasingly point to modifiable risk factors, especially dietary patterns, as potential tools to prevent or delay neurodegeneration. This review evaluates the impact of the MIND diet on the prevention and progression of AD and compares it with other dietary interventions.

PATIENTS AND METHODS: Materials and Methods: A literature search was conducted using the PubMed and Google Scholar databases for articles published from January 2015 to January 2025, focusing on the influence of the MIND diet, as well as other dietary patterns, on AD progression and cognitive performance.

CONCLUSION: Conclusions: While the MIND diet shows promise as a feasible non-pharmacological strategy, current evidence is largely observational and limited by population heterogeneity and inconsistent adherence definitions. Short-term randomized controlled trials are less conclusive. Long-term clinical trials are needed to establish causality. Despite these limitations, the MIND diet remains a practical and potentially effective approach to reducing cognitive decline and delaying the onset of AD.},
}

Humans
*Alzheimer Disease/prevention & control/diet therapy
*Diet

@article {pmid41956136,
year = {2026},
author = {More, PS and Rangari, SW and Lade, SN and Unidrwade, DS and Burle, SS and Umekar, MJ and Lohiya, RT and Zanwar, AS},
title = {Drug Repurposing in Alzheimer's Disease: Emerging Therapeutic Strategies and Promising Candidates.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103113},
doi = {10.1016/j.arr.2026.103113},
pmid = {41956136},
issn = {1872-9649},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder, and the most common cause of dementia, which causes 60 to 70 percent of the cases worldwide, and its prevalence is increasing by more than 55 million people globally, with an expected increase of 139 million cases by 2050. AD is characterized by Amyloid-β plaque deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and oxidative stress, which makes the pathophysiology multifactorial and complex in terms of the development of therapeutic treatment. Existing approved therapies, such as cholinesterase enzyme inhibitors and NMDA receptors antagonists, are merely symptomatic, whereas novel anti-amyloid monoclonal antibodies approved recently have low clinical efficacy with safety and cost issues. The dismal success rates of clinical trials highlight the necessity of alternative approaches. Repurposing of drugs has proved to be a prospective solution, which uses drugs with established safety profiles to speed up the discovery of therapeutic solutions. Repurposed agents are used targeting diverse pathologic pathways, including amyloid aggregation, tau pathology, neuroinflammation, and synaptic dysfunction, with antidiabetic agents (metformin, GLP-1 receptor agonists) and anti-hypertensives (candesartan), anti-inflammatory ones (NSAIDs, pioglitazone), and neuroprotective ones (minocycline, sildenafil). Notably, mitochondrial dysfunction is becoming a significant early and essential cause of AD development, and mitochondria-targeted therapeutics like SS-31, Mdivi-1, MitoQ, DDQ, and SkQ1 are currently considered promising disease-modifying options. The development of artificial intelligence, multi-omics, and precision medicine also improves drug repurposing plans. Overall possibility to integrate multi-target repurposed therapies with novel technologies is a promising prospect to overcome the available shortcomings and improve clinical outcomes in AD.},
}

@article {pmid41945082,
year = {2026},
author = {Falangola, MF and Voltin, J and Cole, M and Nietert, PJ and Liu, F and Iqbal, K and Jensen, JH},
title = {Corrigendum to Diffusion MRI measures detect brain microstructure changes due to early treatment with neurotrophic peptide mimetic P021 in the 3xTg-AD mouse model of Alzheimer's disease. Magn Reson Imaging. 2026 Jun;129:110641 Page: 9.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110677},
doi = {10.1016/j.mri.2026.110677},
pmid = {41945082},
issn = {1873-5894},
}

@article {pmid41946054,
year = {2026},
author = {Tang, S and Peng, Y and Li, Y and Li, Y and Sun, H and Piao, S and Liu, Z and Wu, Y and Hou, Z and Liu, Z and Liu, S and Wang, R},
title = {Congming decoction alleviates Alzheimer's Disease induced by Aβ25-35 in rats via the microbiota-metabolism-inflammation axis, demonstrating its formulation advantages.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158139},
doi = {10.1016/j.phymed.2026.158139},
pmid = {41946054},
issn = {1618-095X},
abstract = {BACKGROUND: Congming decoction (CMD) is a traditional Chinese herbal formulation traditionally employed for enhancing memory. Despite its historical use, the specific mechanisms and advantages of CMD in the context of Alzheimer's disease (AD) remain inadequately understood.

PURPOSE: This study seeks to elucidate the therapeutic effects of CMD on AD in rats induced by Aβ25-35 and to clarify its underlying process through a multi-perspective approach.

STUDY DESIGN AND METHODS: Cognitive function and pathological alterations were assessed using behavioral tests, hematoxylin and eosin (HE) staining, and immunohistochemistry. Fecal metabolomics analysis, conducted via ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS), was utilized to investigate CMD's impact on metabolic disorders. The structure of the gut microbiota was analyzed through 16S rRNA sequencing. Short-chain fatty acids (SCFAs) and bile acids (BAs) in feces, serum, and brain tissue were quantified using gas chromatography-mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography-tandem quadrupole mass spectrometry (UHPLC-TQ-MS). To establish causal relationships, experiments involving antibiotic-induced microbiota depletion (ABX) and fecal microbiota transplantation (FMT) were performed. Network pharmacology and molecular docking techniques were also employed to identify potential active components and targets. Inflammatory markers were evaluated using enzyme-linked immunosorbent assay (ELISA) kits, immunohistochemistry, and immunofluorescence in brain tissue.

RESULTS: CMD markedly enhanced learning and memory, mitigated pathological changes in the brain and colon, and reestablished gut microbiota equilibrium. It regulated 45 endogenous metabolites involved in BAs, α-linolenic acid, and linoleic acid metabolism. CMD also modulated the levels of SCFAs and BAs in fecal matter, serum, and brain tissue. Strong correlations were identified among gut microbiota, metabolites, and AD-related indicators. Antibiotic treatment inhibited the neuroprotective benefits of CMD, whereas FMT from CMD-treated donors successfully replicated its therapeutic benefits. Network pharmacology analysis indicated that the active components of CMD might target inflammatory pathways. Additionally, CMD exhibited a significant restorative impact on markers associated with the AKT/NF-κB signaling pathway.

CONCLUSION: CMD exerts anti-AD effects by modulating the microbiota-gut-brain axis through remodeling gut microbiota, regulating metabolic homeostasis, and reducing brain inflammation. Notably, CMD demonstrated superior efficacy compared to single herbs or herb pairs.},
}

@article {pmid41948063,
year = {2026},
author = {Yang, SO and Ahn, J and Jung, YH and Jang, H and Na, DL and Kim, H and Kim, JP and Seo, SW and Kwak, K},
title = {Deep learning-based detection of cerebral microbleeds on 2D T2*-weighted GRE MRI: toward ARIA-H risk assessment in Alzheimer's treatment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729422},
pmid = {41948063},
issn = {1663-4365},
abstract = {BACKGROUND: Amyloid-related imaging abnormalities with hemorrhage (ARIA-H) are a key safety concern in anti-amyloid therapies for Alzheimer's disease, as they are radiologically indistinguishable from cerebral microbleeds (CMBs). Accurate detection of CMBs is therefore essential for both treatment eligibility assessment and post-treatment safety monitoring. However, manual identification on 2D T2*-weighted gradient-recalled echo (GRE) MRI is labor-intensive and subject to variability.

OBJECTIVE: To develop and validate an artificial intelligence (AI)-based model for automated CMB detection using only 2D T2*-weighted GRE MRI, which is widely used in clinical settings.

METHODS: We implemented a YOLOv11-based deep learning model, preceded by a novel multi-channel preprocessing pipeline that enhances CMB visibility. The model was trained and tested using a dataset of 758 participants, with expert consensus used as the reference standard.

RESULTS: Using the optimized basic preprocessing with super-resolution (BP + SR) pipeline, the model achieved a lesion-level sensitivity of 0.694, precision of 0.705, and F1-score of 0.699. In patient-level analysis for detecting elevated CMB burden (≥4), the system demonstrated sensitivity of 0.933 and specificity of 0.935, supporting reliable stratification of CMB severity. Regional analysis showed sensitivity of 0.625 for lobar CMBs and 0.627 for deep structures.

CONCLUSION: This study demonstrates the feasibility of robust CMB detection using only 2D T2*-weighted GRE MRI. Based on current performance, we position this system as a decision-support tool for GRE-based CMB screening, in which lesion-level detections may be aggregated to inform patient-level CMB burden relevant to ARIA-H risk stratification, while final ARIA grading and clinical decisions require expert neuroradiological confirmation.},
}

@article {pmid41948065,
year = {2026},
author = {Oh, H and Kim, H and Kang, H and Kwon, D and French, L and Park, YH and Youn, YC and An, SS and Kim, S and Kang, S},
title = {Systemic proteomic and organ aging signatures associated with plasma Aβ oligomerization in a Korean cohort: a cross-sectional study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1620991},
pmid = {41948065},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) in the brain, which begins decades before the appearance of clinical symptoms. Blood from AD patients, when spiked with synthetic Aβ, exhibited a higher Aβ oligomerization tendency (OAβT) than the non-AD subjects. OAβT reflected early pathological changes of AD and is considered as a promising blood-based biomarker. However, the mechanism underlying OAβT remained elusive. This study aimed to identify proteomic signatures associated with OAβT and explore its role in AD diagnosis.

METHODS: Forty AD and non-AD subjects from a Korean cohort were divided into four groups based on the disease diagnosis, OAβT values (thresholded at 0.78 ng/mL), and amyloid PET status (A-PET): A-PET-positive AD patients with high or low OAβT values, A-PET-negative non-AD subjects with high or low OAβT values. Using aptamer-based proteomics, 7,288 proteins from plasma samples were quantified, and the group differences were assessed in protein levels and the enrichment of gene sets associated with annotations from the Gene Ontology database. Further, we assessed whether OAβT-PET mismatched cases (A-PET-positive but OAβT-low or A-PET-negative but OAβT-high) exhibited distinct blood proteome signatures in comparison to typical AD cases. Aging signatures for 11 organs were analyzed to explore systemic factors linked to OAβT-PET discrepancies. Additionally, the pharmacological influences on the OAβT-related proteome were investigated by comparing OAβT-correlated proteins with a database of drug-induced proteomic changes.

RESULTS: Elevated OAβT values, regardless of AD diagnosis, correlated with increased immune response and decreased cellular metabolism. Dementia-predicting proteins were enriched in non-AD individuals with high OAβT. Accelerated muscle aging was associated with high OAβT values and worse cognitive function. Furthermore, several potential pharmacological modulators of OAβT, including Minocycline and Anamorelin, were identified.

CONCLUSION: Our findings demonstrated OAβT as a reflection of systemic changes linked to early AD pathology. Moreover, the influence of medications and systemic aging on OAβT values pointed to the potential avenues for intervention and emphasized the importance of considering systemic factors in AD pathogenesis and treatment.},
}

@article {pmid41948540,
year = {2026},
author = {Khorsand, B and Ghanbarian, E and Rabin, LA and Sajjadi, SA and Ezzati, A},
title = {Incremental value of plasma biomarkers in predicting clinical decline among cognitively unimpaired older adults: Results from the A4 trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70321},
pmid = {41948540},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults.

METHODS: We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E (APOE) ε4, amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR), plasma phosphorylated tau-217 (p-tau217), and Preclinical Alzheimer's Cognitive Composite (PACC) were assessed. A sub-study of 656 participants evaluated added value of plasma amyloid beta (Aβ)42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

RESULTS: The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%).

DISCUSSION: The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD.},
}

@article {pmid41948553,
year = {2026},
author = {Sólyomvári, C and Makkai, G and Capelo-Carrasco, N and Strac, DS and Zelena, D and Farkas, S},
title = {Time-dependent histological characterization of amyloid-β induced cholinergic and glial alterations and their modulation by dehydroepiandrosterone sulfate (DHEAS).},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1764298},
pmid = {41948553},
issn = {1664-2392},
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; Male ; *Neuroglia/drug effects/pathology/metabolism ; Mice ; *Cholinergic Neurons/drug effects/pathology/metabolism ; Mice, Inbred C57BL ; *Dehydroepiandrosterone Sulfate/pharmacology ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Peptide Fragments/toxicity ; Microglia/drug effects/pathology/metabolism ; Time Factors ; *Basal Nucleus of Meynert/drug effects/pathology/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by predominant - but not exclusive - pathological accumulation of amyloid-β (Aβ) in the brain. This process affects not only neurons (particularly cholinergic) but also glial cells, contributing to progressive neuronal loss and neuroinflammation. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are endogenous steroids that are hypothesized to exert neuroprotective and anti-inflammatory effects. This study aims to histologically characterize the in vivo temporal progression of Aβ-induced alterations in cholinergic neurons and glial morphology. Our secondary aim was to evaluate whether DHEAS protects cholinergic integrity and, if so, whether this effect is mediated through glial activation.

METHODS: Aβ1-42 was injected into the cholinergic nucleus basalis magnocellularis (NBM) region of C57BL6/J male mice and one hour later 10 mg/kg DHEAS or vehicle (0.9% saline) was applied intraperitoneally. After 3, 12 or 33 days, the mice were transcardially perfused and immunohistochemical staining was used to investigate cholinergic cell (ChAT) and fiber (AChE) loss, as well as microglia (IBA1) and astrocyte (GFAP) morphology.

RESULTS: Our findings confirmed that Aβ peptide exerted neurotoxic effects on the cholinergic system and triggered time-dependent activation in both glia cell types. Microglial cells initiated their response by day 3, adopting an amoeboid morphology, whereas delayed astrocytic reactivity was observed between days 3 and 12, demonstrated by increased ramification. DHEAS treatment preserved cholinergic fiber density, without effecting the number of cell bodies and modulated the inflammatory responses of glia cells, by decreasing the area occupied and number of microglia in a time dependent manner.

DISCUSSION: Aβ toxicity exerts time-dependent effects on both cholinergic neurons and glia cells, while DHEAS shows therapeutic promise, though its efficacy and exact mechanism require further investigation.},
}

Animals
*Amyloid beta-Peptides/toxicity
Male
*Neuroglia/drug effects/pathology/metabolism
Mice
*Cholinergic Neurons/drug effects/pathology/metabolism
Mice, Inbred C57BL
*Dehydroepiandrosterone Sulfate/pharmacology
*Alzheimer Disease/pathology/metabolism/drug therapy
*Peptide Fragments/toxicity
Microglia/drug effects/pathology/metabolism
Time Factors
*Basal Nucleus of Meynert/drug effects/pathology/metabolism

@article {pmid41948610,
year = {2026},
author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Ashique, S and Islam, A},
title = {Nanoengineered phytochemicals overcome blood-brain barrier constraints in neurodegenerative disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1792829},
pmid = {41948610},
issn = {1664-2295},
abstract = {Neurodegenerative disorders represent a growing global health burden and remain largely incurable, with current therapies providing only symptomatic relief and limited disease modifications. A major obstacle to effective treatment is the inability of many neuroprotective agents to reach the brain at therapeutically relevant concentrations due to poor bioavailability and the restrictive nature of the blood-brain barrier. Plant-derived phytochemicals possess well-documented antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities; however, their clinical translation has been hindered by physicochemical instability, rapid metabolism, and insufficient brain exposure. This review critically examines nanoengineered delivery systems as a strategy to overcome these limitations and enable the effective brain targeting of neuroprotective phytochemicals. By integrating mechanistic insights with preclinical and emerging clinical evidence, we compared lipid-based, polymeric, vesicular, and dendritic nanocarriers, highlighting how particle size, surface chemistry, and ligand functionalization govern blood-brain barrier transport and intracerebral distribution. Particular emphasis is placed on rational design principles that consistently enhance brain bioavailability and therapeutic efficacy across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and related disorders. Beyond efficacy, we analyzed key translational challenges, including nanocarrier-associated neurotoxicity, standardization of herbal activities, and regulatory gaps unique to herbal nanomedicines. Collectively, this synthesis reframes nano-phytomedicine not as an incremental formulation upgrade but as a design-driven strategy capable of unlocking the therapeutic potential of phytochemicals for neurodegenerative disease management.},
}

@article {pmid41949026,
year = {2026},
author = {Boyd, RJ and Dong, D and Sagar, R and Iliuk, A and Ahmed, W and Androni, X and Porsteinsson, AP and Rosenberg, PB and Lyketsos, CG and Witwer, KW and Mahairaki, V},
title = {Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71273},
doi = {10.1002/alz.71273},
pmid = {41949026},
issn = {1552-5279},
support = {1RF1AG083801/GF/NIH HHS/United States ; AGR01054771/AG/NIA NIH HHS/United States ; AGR01050515/AG/NIA NIH HHS/United States ; AGR01046543/AG/NIA NIH HHS/United States ; AGR01071522/AG/NIA NIH HHS/United States ; //The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Extracellular Vesicles/metabolism ; *Organoids/metabolism ; *Proteomics ; *Brain/metabolism/pathology ; Biomarkers/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; Female ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) exhibits high genetic and clinical heterogeneity that limits therapeutic success. Patient-derived brain organoids and their extracellular vesicles (EVs) provide physiologically relevant models to study disease mechanisms and individualized drug responses.

METHODS: We generated the largest brain organoid cohort to date, derived from 30 independent induced pluripotent stem cell (iPSC) lines from AD and control individuals. Comparative proteomic profiling was performed on both organoids and their secreted EVs to capture molecular diversity and treatment effects.

RESULTS: Organoids and EVs consistently recapitulated neuronal proteomic signatures and revealed early alterations in AD-related pathways, including synaptic and neurotransmitter dysfunction. Distinct proteomic responses mirrored individual variability in selective serotonin reuptake inhibitor sensitivity.

DISCUSSION: Integrating organoid and EV data provides a systems-level view of AD pathophysiology and treatment response, positioning this dual-platform model as a cost-effective tool for precision medicine and drug discovery.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
*Extracellular Vesicles/metabolism
*Organoids/metabolism
*Proteomics
*Brain/metabolism/pathology
Biomarkers/metabolism
Induced Pluripotent Stem Cells/metabolism
Male
Female

@article {pmid41942439,
year = {2026},
author = {Ohya, T and Arakawa, R and Sakayori, T and Nogami, T and Uchiyama, S and Tateno, A},
title = {Tau accumulation increases the susceptibility to effective seizures of electroconvulsive therapy.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04016-3},
pmid = {41942439},
issn = {2158-3188},
abstract = {Electroconvulsive therapy (ECT) is a very valuable treatment for mood disorders. While previous studies have examined predictors of ECT responsiveness, there is a scarcity of neuroimaging studies examining these predictors. In previous studies, it has been reported that epilepsy is significantly more common in patients with Alzheimer's disease, and it has been suggested that tau accumulation is related to the susceptibility to seizures. Positron emission tomography (PET) with florzolotau (18 F) ([[18]F]PM-PBB3) allows accurate quantification of tau in the brain cortex. We therefore performed tau PET with florzolotau (18 F) in 14 patients with mood disorders undergoing ECT to determine whether there is a relationship between tau accumulation and susceptibility to ECT. As a result, we found that the more tau accumulates, the more likely it is to produce effective seizures in ECT. Although our study has some limitations, it is suggested that ECT would be the first choice for treatment of depression associated with degenerative pathology such as Alzheimer's disease because tau accumulation might enhance the therapeutic efficacy of ECT.},
}

@article {pmid41942585,
year = {2026},
author = {Jahanbani, P and Hosseinzadeh, L and Mahmoudi, M and Jalilian, F and Eftekhari, M and Modarresi, M},
title = {Beyond the root: licorice (Glycyrrhiza glabra L.) fruit extract modulates oxidative stress and apoptotic markers in PC12 cells.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-46382-4},
pmid = {41942585},
issn = {2045-2322},
support = {4020639//Kermanshah University of Medical Sciences/ ; },
abstract = {The rising global prevalence of neurodegenerative disorders underscores the urgent need for novel therapeutic strategies. Oxidative stress is a well-established central driver in the pathogenesis of conditions like Alzheimer's and Parkinson's disease. While the root of Glycyrrhiza glabra L. (licorice) is a renowned source of natural antioxidants, its fruit remains a largely unexplored reservoir of bioactive compounds with potential neuroprotective properties. This in vitro study aimed to systematically evaluate the neuroprotective potential of different licorice fruit extracts and elucidate the underlying mechanisms against hydrogen peroxide (H2O2)-induced oxidative damage in PC12 neuronal cells. Different licorice fruit extracts were prepared sequentially with n-hexane, chloroform, ethyl acetate, methanol, and water by the maceration method. The protective effects of these extracts against H2O2-induced cytotoxicity were assessed using the MTT assay. Phytochemical profiling of the active ethyl acetate extract (EA extract) was performed using TLC, total flavonoid assay, and HPLC-DAD. EA extract exhibited the strongest protective activity. Pre-treatment with non-toxic concentrations of EA extract (12.5 and 25 µg/mL) significantly increased cell viability against H2O2 (IC50 = 70 µg/mL approximately 2.06 mM) by 33% and 38%, respectively. This extract possessed the highest total flavonoid content (50.08 ± 0.31 mg of quercetin equivalents per gram of dry extract) among all extracts, and HPLC-DAD analysis confirmed the presence of glabridin 27.75 ± 0.01 mg per gram of dry EA extract. EA extract also notably restored mitochondrial membrane potential, reduced caspase-3 activity, and decreased ROS production in H2O2-stressed cells. Our findings indicate that the ethyl acetate extract of licorice fruit attenuates H2O2-induced oxidative stress in PC12 cells, and its neuroprotective effect is likely associated with its high flavonoid content. Further research on licorice fruit may facilitate the discovery of novel therapeutic agents for oxidative stress-related disorders.},
}

@article {pmid41944296,
year = {2026},
author = {Gong, W and Hui, W and Qiao, S and Ji, Q and Liu, M and Zhang, B and Liu, D and Wu, Y and Zhou, S},
title = {Brain and Liver Dual-Targeting Oridonin Nanoparticles to Enhance Aβ Clearance for Alzheimer's Disease Therapy.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23458},
doi = {10.1002/advs.202523458},
pmid = {41944296},
issn = {2198-3844},
support = {2023-ZDYJSY-001//Shaanxi Administration of Traditional Chinese Medicine/ ; 2023JSYX16//Research Project from Air Force Medical University/ ; //Key Laboratory of New Drug Delivery System and New Technology for Formulation/ ; 82073775//National Natural Science Foundation of China/ ; 82071515//National Natural Science Foundation of China/ ; SZY-KJCYC-2025-ZY-013//Scientific Research Project of Shaanxi Administration of Traditional Chinese Medicine/ ; },
abstract = {The brain and liver are both critical organs involved in the pathogenesis of Alzheimer's disease (AD), particularly in the modulation of amyloid-beta (Aβ) metabolism and neuroinflammation. Based on this, a multifunctional nanodrug delivery system, termed OAF, was developed by encapsulating oridonin (ORI) into apoferritin (ApoFn), enabling simultaneous targeting of both brain and the liver through transferrin receptor 1 (TfR1). OAF upregulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) in cerebral capillary endothelial cells and hepatic parenchymal cells to promote Aβ clearance from the brain and subsequent hepatic degradation. In AD mice, OAF treatment markedly reduced Aβ deposition, neuroinflammation, and cognitive impairment, while ameliorating inflammation, oxidative stress, and mitochondrial dysfunction in both brain and liver. Overall, OAF synergistically combined Aβ clearance, anti-inflammatory, and antioxidant mechanisms, offering a novel therapeutic strategy for AD.},
}

@article {pmid41936874,
year = {2026},
author = {Wang, YX and Zhou, XW and Du, WR and Qin, SH and Zhang, CY and Ma, ZY},
title = {Novel 2-aminopyrimidine carboxamide derivatives as potential anti-Alzheimer's disease agents: Design, synthesis, biological activity and computational simulation evaluation.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130650},
doi = {10.1016/j.bmcl.2026.130650},
pmid = {41936874},
issn = {1464-3405},
abstract = {In this study, a series of 2-amino-5-formamidopyrimidine derivatives were designed and synthesized. Their potential as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD) were evaluated by the Ellman method. Meanwhile, the antioxidant activity of these compounds were assessed by the DPPH (2,2-diphen-yl-1-picrylhydrazyl) free radical scavenging assay. The cholinesterase (ChE) inhibition test showed that most compounds exhibited excellent to moderate inhibitory effects on acetylcholinesterase (AChE), while most of them did not show significant inhibitory effects on butyrylcholinesterase (BuChE), demonstrating significant selectivity. Among them, compound 9 s (AChE: IC50 = 1.60 μM) whose AChE inhibitory activity is superior to the positive control galantamine (AChE: IC50 = 5.10 μM) is the most promising representative compound. Meanwhile, compound 9 s has high selectivity with a SI (IC50 ratio of BuChE to AChE) value of 29.85. The results of enzyme kinetics study determined that compound 9 s was a mixed-type inhibitor. Additionally, the molecular docking studies results indicated that compound 9 s could simultaneously interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, which was consistent with the results of the enzyme kinetics experiments. Molecular dynamics (MD) simulation study further verified the stability of the 9 s-AChE complex. In addition, the DPPH radical scavenging assay indicated that these compounds also possessed relatively weak antioxidant activities. Among them, compound 9p exhibited the best antioxidant activity with an IC50 value of 113.93 μM, which was lower than that of the positive control ascorbic acid (IC50 = 41.17 μM). Overall, these experimental results suggested that compound 9 s as AChE inhibitor had potential value for further research.},
}

@article {pmid41936993,
year = {2026},
author = {Lizard, G and Sassi, K and Mackrill, JJ and Ghzaiel, I and Meziane, S and Hassen, E and Abdelkarim, M and Masmoudi-Kouki, O and Ghrairi, T and Brahmi, F and Gargouri, A and Rezig, L and Benkalifa, R and Khallouki, F and El Midaoui, A and Pincemail, J and Atanasov, AG and Vejux, A and Millot, N},
title = {7-ketocholesterol as a theranostic target: potential applications and future perspectives.},
journal = {Chemistry and physics of lipids},
volume = {},
number = {},
pages = {105588},
doi = {10.1016/j.chemphyslip.2026.105588},
pmid = {41936993},
issn = {1873-2941},
abstract = {7-Ketocholesterol (7KC) is mainly formed by cholesterol autoxidation and is a pro-oxidant and pro-inflammatory bioactive lipid that also induces different types of cell death, including oxiapoptophagy. It is frequently associated with major age-related diseases, such as cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease. 7KC can therefore be considered a biomarker for these diseases, offering the possibility of developing theranostic strategies combining diagnosis and treatment. Currently, all the elements are in place to develop tools for the design of theranostic therapies targeting 7KC in diseased organs: antibodies, nanoparticles used as nanoplatforms, molecules that neutralize 7KC such as enzymes which degrade it, as well as natural or synthetic compounds that inhibit the cytotoxic signaling pathways associated with oxidative stress, inflammation and cell death activated by 7KC. Identifying and neutralizing 7KC biological activities using a theranostic approach could also be of interest for growing medical fields such as space medicine widely concerned by oxidative stress, aging and age-related diseases, driven by microgravity. This review supports that most of key tools are now available to develop theranostic treatments targeting 7KC in age-related pathologies, especially in cardiovascular diseases associated with atheroma, but also in age-related macular degeneration and Alzheimer's disease. Discovery of effective treatments for these diseases is a major challenge and will answer an important need for both patients and caregivers.},
}

@article {pmid41937403,
year = {2026},
author = {Borda, MG and O'Hara-Veintimilla, K and Aarsland, D},
title = {Older Adults, Anti-Amyloid Therapy, and Frailty: What Oncology Can Teach Us.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70567},
doi = {10.1111/ene.70567},
pmid = {41937403},
issn = {1468-1331},
support = {//Helse Vest/ ; //Nasjonalforeningen for Folkehelsen/ ; },
mesh = {Humans ; *Frailty/diagnosis ; Aged ; *Geriatric Assessment/methods ; *Alzheimer Disease/drug therapy ; *Medical Oncology/methods ; Clinical Decision-Making ; Frail Elderly ; },
abstract = {BACKGROUND: Anti-amyloid therapies, such as lecanemab or donanemab, represent the first disease-modifying treatments approved for early Alzheimer's disease (AD) in individuals with confirmed amyloid pathology. Their implementation in routine care raises important challenges, particularly in older adults with heterogeneous functional reserve and multimorbidity. We address the role of frailty in refining clinical decision-making for anti-amyloid therapies.

METHODS: This short communication presents a conceptual discussion informed by geriatric oncology, where frailty assessment and comprehensive geriatric assessment (CGA) are routinely used to individualize treatment in heterogeneous older populations. We describe how similar principles may be applied to anti-amyloid monoclonal antibodies once regulatory eligibility has been established, and outline a frailty-informed conceptual framework to support clinical decision-making in routine care.

RESULTS: This conceptual analysis proposes a stepwise, frailty-informed clinical framework that integrates regulatory eligibility assessment with brief frailty screening and targeted comprehensive geriatric assessment. The framework defines differentiated clinical pathways for robust, pre-frail, and frail individuals, linking frailty status to specific decisions regarding treatment initiation, need for prehabilitation, intensity of monitoring, and consideration of treatment deferral. By embedding frailty assessment within routine clinical workflows, the framework operationalizes evaluation of physiological reserve, anticipates treatment burden and monitoring feasibility, and provides a structured approach to individualized risk-benefit appraisal for anti-amyloid therapies.

CONCLUSIONS: Frailty-informed frameworks may offer a pragmatic and ethically grounded approach to support real-world implementation of anti-amyloid therapies, guiding treatment selection as well as longitudinal decisions on monitoring, continuation, and reassessment over time.},
}

Humans
*Frailty/diagnosis
Aged
*Geriatric Assessment/methods
*Alzheimer Disease/drug therapy
*Medical Oncology/methods
Clinical Decision-Making
Frail Elderly

@article {pmid41937689,
year = {2026},
author = {Helphrey, JH and Hart, J and McClintock, SM and Peters, ME and Thakkar, VJ and LoBue, C},
title = {A scoping review of frontal cortex tDCS on neuropsychological functioning in older adults with mild cognitive impairment and Alzheimer's Clinical Syndrome.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/09540261.2026.2647921},
pmid = {41937689},
issn = {1369-1627},
abstract = {Mild cognitive impairment (MCI) and Alzheimer's Clinical Syndrome (ACS) are prevalent, incurable, and are expected to increase in incidence over the next 30 years. Finding new treatments to address the cognitive and behavioral problems in MCI and ACS represent an urgent need. Brain circuitry disruption can cause cognitive dysfunction and neuropsychiatric symptoms (NPS) in both MCI and ACS. Therefore, one promising avenue of treatment is non-invasive brain stimulation through transcranial direct current stimulation (tDCS). This scoping review examined the current knowledge base for the potential neuropsychological and neuropsychiatric effects of frontal cortex tDCS in older adults with MCI and ACS. Of the 17 randomized controlled trials reviewed, treatment parameters such as session length, current intensity, number of treatments, and time between treatments varied widely across studies, which restricted identification of optimal tDCS treatment protocols. Mixed findings on neuropsychological outcomes were observed, though significant improvements were most commonly seen in studies measuring global cognition (10) followed by executive function (6). Only three studies yielded clinically significant cognitive improvement, and few studies assessed NPS outcomes. Additional rigorous research is indicated to enhance our understanding of tDCS as a treatment for cognitive and neuropsychiatric symptoms in older adults with MCI and ACS.},
}

@article {pmid41937703,
year = {2026},
author = {Salim, MW and Zhang, W and Collins-Praino, L and Wang, Y and Care, A},
title = {Small Extracellular Vesicles from Neural Cells: Physiological and Pathological Roles, and Potential in Neurodegenerative Therapy.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e04608},
doi = {10.1002/adhm.202504608},
pmid = {41937703},
issn = {2192-2659},
support = {//Higher Education Commission/ ; //International Macquarie University Research Excellence Scholarship/ ; FT210100737//ARC Future Fellowship/ ; //Dementia Australia Research Foundation/ ; //Mason Foundation/ ; //National Foundation for Medical Research & Innovation/ ; },
abstract = {Small extracellular vesicles (sEVs) have emerged as central mediators of intercellular communication in the central nervous system (CNS) and are increasingly recognized for their dual roles in the pathogenesis and treatment of neurodegenerative diseases (NDDs). In disease contexts, sEVs facilitate the intercellular dissemination of pathogenic proteins and nucleic acids, thereby contributing to the propagation of Alzheimer's disease (AD) and Parkinson's disease (PD) pathology. Conversely, their intrinsic biocompatibility, capacity to traverse brain barriers, and inherent organotropic properties position sEVs as highly promising nanocarriers for CNS drug delivery. While mesenchymal stem cell-derived sEVs have been widely investigated in preclinical NDD models, accumulating evidence suggests that sEVs derived from neural cells, including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes, and brain endothelial cells may offer superior brain targeting, disease relevance, and functional efficacy. This review provides a comprehensive and critical analysis of current knowledge on neural cell-derived sEVs, encompassing their physiological roles in brain homeostasis, their involvement in AD and PD pathogenesis, and their emerging therapeutic applications. We discuss cell-type-specific sEV cargo profiles, mechanisms underlying blood-brain and blood-cerebrospinal fluid barrier traversal, and recent advances in endogenous and exogenous engineering strategies that enhance cargo loading, targeting precision, and therapeutic performance. Importantly, we address key translational challenges that currently limit clinical implementation. By integrating mechanistic insights with therapeutic and engineering perspectives, this review highlights neural cell-derived sEVs as a biologically informed and versatile platform, underscoring their potential to advance next-generation neuro-nanomedicine for NDDs.},
}

@article {pmid41940797,
year = {2026},
author = {Rus Prelog, P and Kores Plesničar, B and Zupan, M and Frol, S and Kramberger, MG},
title = {The value and risks of antidepressant therapy in Alzheimer's disease: a field update and its clinical implications.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/14737175.2026.2653170},
pmid = {41940797},
issn = {1744-8360},
abstract = {INTRODUCTION: Depression is one of the most frequent and disabling neuropsychiatric syndromes in Alzheimer's disease (AD), yet antidepressant use is still largely extrapolated from late‑life depression and is poorly aligned with emerging evidence on 'neurodegenerative depression' and disease‑modifying therapies. This article critically re‑examines the clinical value and risks of antidepressants in AD.

AREAS COVERED: Drawing on a narrative search of PubMed/MEDLINE and Embase (January 2000-December 2025) and targeted review of recent guidelines and anti‑amyloid trials, the article synthesizes randomized and observational data on efficacy and safety across antidepressant classes, highlighting modest and inconsistent benefits alongside adverse outcomes such as falls, hyponatremia, bleeding, mortality and possible acceleration of cognitive decline. It integrates mechanistic work on synaptic loss, neuroinflammation and network disruption, discusses the exclusion of depressed patients from anti‑amyloid trials, and reviews rapid‑acting, neuromodulatory and psychosocial strategies within a proposed precision‑prescribing framework based on biomarkers, vascular burden and symptom dimensions.

EXPERT OPINION: Monoaminergic antidepressants in AD should not be abandoned but repositioned as time‑limited, closely monitored options for clearly defined, functionally impairing depressive syndromes, embedded in multimodal care rather than used as default, long‑term treatment for non‑specific distress. Future priorities include biomarker‑stratified AD depression trials, evaluation of interactions with anti‑amyloid therapies and rigorous testing of non‑monoaminergic interventions.},
}

@article {pmid41940869,
year = {2026},
author = {Sharif-Askari, Z and Atoui, K and El Zein, W and Rizk, M and Sharif Askari, E},
title = {From periodontitis to neurodegeneration: Can probiotics modulate the P. gingivalis-amyloid pathway in Alzheimer's disease?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261432686},
doi = {10.1177/13872877261432686},
pmid = {41940869},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the gradual destruction of cognitive and behavioral functions. Despite the continuous research efforts, there is still no cure for this disease. In recent years, researchers have investigated Porphyromonas gingivalis (P. gingivalis) as a potential cause of AD. P. gingivalis-lipopolysaccharides (LPS) and gingipains have been implicated in neuroinflammatory cascades relevant to AD. The gut-brain axis provides a pathway for microbial migration, immune activation, and regulation of the central nervous system function. Emerging evidence suggests that selected probiotics may modulate these pathways by restoring microbial balance, reinforcing epithelial barrier function, and regulating innate and adaptive immunity. Importantly, much of the evidence and mechanistic support for these effects derives from preclinical and animal studies, whereas human data remain limited to associative findings and early-stage clinical trials. Early clinical trials report modest improvements in cognitive scores and systemic inflammatory markers. Strain selection, dose, and treatment duration make direct comparisons challenging. This review integrates the literature on the links between P. gingivalis and AD, suggesting that probiotics may be used as neuroprotective agents. Taken together, current preclinical signals are consistent with the potential of probiotics as feasible adjuncts, pending confirmatory trials with standardized formulations.},
}

@article {pmid41941206,
year = {2026},
author = {Andrews, SJ and Yaffe, K},
title = {Advancing Precision Dementia Care With Genetic-Exposome Risk Assessment.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0573},
pmid = {41941206},
issn = {2168-6157},
}

@article {pmid41941234,
year = {2026},
author = {Oo, WJ and Sia, WT and Lee, JY and Chen, CH and Chang, WL and Chye, SM},
title = {The Role of Presynaptic Cytomatrix Protein Bassoon (BSN) in Tau Pathology and Propagation.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273400895251129055504},
pmid = {41941234},
issn = {1996-3181},
abstract = {Neurodegenerative disorders have become a global health threat following a prolonged lifespan, with the majority involving the accumulation and propagation of pathological tau. Tau oligomers can migrate to presynaptic terminals and interact with surrounding proteins, among which Bassoon (BSN) is one that selectively binds to and colocalises with misfolded tau. Studies have reported numerous implications of BSN mutations in tau pathology, including promoting tau seeding activity, hyperphosphorylation, misfolding, and aggregation. These eventually lead to the formation of neurofibrillary tangles in tauopathies. Given the BSN's physiological role in maintaining synapses, its mutation also impairs synaptic integrity. These abnormalities are consistently attenuated by downregulating BSN levels. However, BSN downregulation can lead to tau hyperphosphorylation via an alternative pathway, CDK5 hyperactivity. Current findings hypothesize that BSN reduces tau clearance by inhibiting proteasome activity. It is also suggested that BSN can impair dopaminergic pathways prior to the detection of tau pathological features. Tunnelling nanotubes also emerge as a potential interneuronal route for BSN-mediated tau spread. Despite a lack of clinical evidence, findings from postmortem samples, in vitro, and preclinical models highlight BSN as a potential candidate for tau-targeting therapies, indicating its role in the pathological development of tau. The involvement of BSN in tau seeding might also resolve challenges posed by tau-targeting drugs during clinical trials. Hence, this article aims to provide new insights into recent findings on BSN and tau with reference to previous studies. We will discuss the possible mechanisms involved, along with the future therapeutic value of BSN in the treatment of tauopathies.},
}

@article {pmid41941239,
year = {2026},
author = {Wang, N and Wen, H and Sun, Y and Xu, W and Shen, X and Wang, R},
title = {Effects of Hesperetin Early Intervention on Brain Neurons and Microglia in APPswe/PS1dE9 Mice.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273418623251203072424},
pmid = {41941239},
issn = {1996-3181},
abstract = {INTRODUCTION: Neuroinflammation and microglial dysfunction play central roles in the pathogenesis of Alzheimer's disease (AD). This study investigated whether early intervention with hesperetin, a citrus flavonoid, could attenuate neuroinflammation and modulate microglial polarization in both wild-type (WT) and APPswe/PS1dE9 transgenic (TG) mice.

METHODS: Three-month-old male C57BL/6J WT and APPswe/PS1dE9 TG mice were administered hesperetin (10 or 20 mg/kg/day for WT; 20, 40, or 80 mg/kg/day for TG) or vehicle for six months. Neuronal morphology was assessed using thionine staining. Microglial polarization was evaluated via CD11b/iNOS and CD11b/Arginase-1 immunofluorescence. Protein expression of CD11b, iNOS, Arginase-1, and TREM2 was measured by Western blot, and cytokine levels (TNF-α, IL-10) were quantified by ELISA.

RESULTS: In WT mice, hesperetin improved neuronal integrity, reduced M1 markers (CD11b⁺/ iNOS⁺ cells, iNOS, TNF-α), and enhanced M2 markers (CD11b⁺/Arginase-1⁺ cells, Arginase-1, TREM2). TG mice exhibited exacerbated neuroinflammation and neuronal loss compared to WT controls, which was significantly mitigated by hesperetin treatment. All hesperetin doses in TG groups reduced pro-inflammatory markers and increased anti-inflammatory and repair-associated factors.

DISCUSSION: These results indicate that hesperetin shifts microglial polarization toward the protective M2 phenotype, potentially via TREM2 upregulation, thereby reducing neuroinflammation and neuronal damage. This effect was observed in both age-related and Aβ-driven pathology, suggesting a dual role for hesperetin in immunomodulation and neuroprotection.

CONCLUSION: Early hesperetin intervention exerts neuroprotective effects by rebalancing microglial polarization and enhancing TREM2 expression, highlighting its potential as a preventive strategy against AD-related neuroinflammation.},
}

@article {pmid41941282,
year = {2026},
author = {Agrawal, MM and Mittal, P},
title = {Emerging Therapies and Research in Alzheimer's Disease: A Critical Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249403872251208145159},
pmid = {41941282},
issn = {1875-6166},
abstract = {Alzheimer's disease, an extremely prevalent neurological illness and the leading cause of dementia globally, is an extremely prevalent neurological illness and is the leading cause of dementia globally. There are a few treatment options for AD, and those that do exist only slightly reduce symptoms, even after several clinical studies. The formation of Aβ plaques, neuroinflammation, and hyperphosphorylated tau neurofibrillary tangles are the characteristics of AD. While monoclonal antibodies such as lecanemab, donanemab, and aducanumab have demonstrated potential in addressing Aβ, their clinical efficacy and safety over an extended period of time remain uncertain. Novel avenues for tackling the underlying genetic causes of AD have been made possible by developments in genome editing tools, most notably CRISPR-Cas9. In preclinical animals, CRISPR-Cas9 has effectively edited genes relevant to AD, such as APP and PSEN1, leading to decreased levels of Aβ and enhanced cognitive function. Additionally, base and prime editing, two precision gene-editing techniques, have increased the medicines' selectivity and decreased their offtarget effects. However, before clinical applications are deployed, challenges related to technology, ethics, and safety must be resolved. This review highlights how monoclonal antibodies, neuroinflammation research, and CRISPR-Cas9 have the potential to revolutionize therapy choices for AD by examining the most current developments in the field.},
}

@article {pmid41941989,
year = {2026},
author = {Sun, Z and Peng, Q and Qiu, C and Jia, X and Wang, H and Wu, S and Tao, W},
title = {A specific Pilose antler peptide LVLVEAELRE ameliorates cognitive deficits in SAMP8 mice via Celsr2.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121649},
doi = {10.1016/j.jep.2026.121649},
pmid = {41941989},
issn = {1872-7573},
abstract = {Pilose antler peptide (PAP), an extract derived from the traditional Chinese medicinal material Pilose antler, has shown promise in the treatment of neurodegenerative diseases. However, the precise molecular mechanisms underlying its anti-Alzheimer's disease (AD) effects remain to be fully elucidated.

AIM OF THE STUDY: This study focuses on a specific PAP monomer with a defined sequence (LVLVEAELRE), herein referred to as PAP, to explore its potential role and molecular mechanisms in AD treatment.

MATERIALS AND METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice were employed to evaluate the effects of PAP on cognitive function, classical AD pathologies (Aβ and p-Tau), and synaptic plasticity. To further elucidate the causal role of Cadherin EGF LAG seven-pass G-type receptor 2 (Celsr2), bidirectional viral manipulations (AAV-shCelsr2 for knockdown and AAV-OECelsr2 for overexpression) were performed in vivo. Furthermore, cellular thermal shift assays (CETSA), molecular docking, and microscale thermophoresis (MST) were utilized to validate the direct interaction between PAP and Celsr2.

RESULTS: PAP administration significantly improved cognitive impairment, mitigated Aβ deposition and Tau hyperphosphorylation, and enhanced synaptic plasticity in SAMP8 mice. Mechanistically, PAP upregulated Celsr2 expression, restored AMPA receptor subunits, and inhibited neuronal senescence. Crucially, Celsr2 knockdown abolished these neuroprotective benefits, whereas Celsr2 overexpression synergistically amplified the therapeutic efficacy of PAP. Finally, MST and docking analyses confirmed that PAP possesses a high and specific binding affinity for WT Celsr2.

CONCLUSIONS: This study demonstrates that PAP ameliorates AD-like pathology by regulating Celsr2, highlighting its potential as a promising preclinical drug candidate. The research findings provide a theoretical basis for the development of PAP-based therapeutic strategies for Alzheimer's disease.},
}

@article {pmid41934929,
year = {2026},
author = {Yao, M and Guo, H and Fang, Y and Chen, Y and Liu, Y and Liu, S and Guo, J and Guo, Z and Qian, J and Ma, Q},
title = {Microplastics released from dental materials induce oral inflammatory bone resorption and apoptosis via mitochondrial dysfunction.},
journal = {Environment international},
volume = {210},
number = {},
pages = {110226},
doi = {10.1016/j.envint.2026.110226},
pmid = {41934929},
issn = {1873-6750},
abstract = {Microplastics (MPs) are emerging pollutants that are associated with many diseases including atherosclerosis, inflammatory bowel disease (IBD), and Alzheimer's. The oral cavity is the primary point for the uptake of MPs by human, where MPs could pose risks to oral and even system health. Various polymer-based materials have been used as dental materials in oral treatment, however, the assessment of MPs in dental treatments remains limited and the processes and mechanisms by which MPs affect human health through the oral route are elusive. Here, we report the assessment of the risks and sources of MPs in dental clinics, the establishment of the relationship between MPs and oral inflammatory disorders, and also the elucidation of underlying mechanisms. Our results showed that commonly used therapeutic dental materials could generate MPs in dental clinics with proportions significantly higher than those in office areas and outdoors. As a representative, polymethyl methacrylate (PMMA) MPs showed significant toxicity to human oral keratinocytes (HOK), human periodontal ligament stem cells (hPDLCs), and THP-1-derived macrophages. Mechanistic investigations of apoptosis and inflammation processes revealed that MPs could lead to mitochondrial stress and autophagy and trigger the Notch signaling pathway and the JAK-STAT signaling pathway. Mice experiments showed that prolonged high-dose MPs exposure induced periodontal inflammatory reactions and even led to inflammatory bone resorption. This study provides a scientific basis for the oral health risks by MPs in dental practice and addresses the need for the development of dental materials with higher biocompatibility and environmentally sustainability.},
}

@article {pmid41935066,
year = {2026},
author = {Shou, R and Wang, Z and Han, Z and Li, A and Shang, J and Lou, H and Zhang, F and Zhan, Y and Shen, G and Lu, X and Jiang, H and Fan, X},
title = {Dietary silver nanoparticle supplementation induces Alzheimer-like lesions through Bifidobacterium deficiency-dominated gut microbiota dysbiosis and neuroinflammation.},
journal = {NPJ science of food},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41538-026-00820-9},
pmid = {41935066},
issn = {2396-8370},
support = {No. LY23B070004//Zhejiang Provincial Natural Science Foundation of China/ ; No. 82374136//National Natural Science Foundation of China/ ; No.2024SDXT001-7//Key R&D Program of Zhejiang/ ; },
abstract = {Dietary supplement silver nanoparticles have recently drawn attention following reports of hazards associated with long-term use. However, their biosafety, especially their effects on the gut-brain axis, remains largely unexplored. This study demonstrated that dietary supplement silver nanoparticles can accumulate in the intestines, brain, and liver of mice. Chronic exposure to these nanoparticles leads to Alzheimer-like lesions, primarily by disrupting gut microbiota balance. Specifically, this exposure depletes Bifidobacterium and Ruminococcaceae, resulting in reduced intestinal metabolites such as sphingomyelin (d18:1/20:0), tryptophan, and indole. Consequently, this disruption causes neuroinflammation, cognitive impairment, and amyloid-β deposition in mice. Moreover, Bifidobacterium was identified as a key microbial group contributing to Alzheimer-like lesions after exposure, whereas supplementation with Bifidobacterium breve MCC1274 effectively alleviated these lesions. Therefore, the potential risks of silver nanoparticles in dietary supplements should be carefully evaluated. This study provides a promising new direction for the prevention and treatment of Alzheimer-like lesions through microbial interventions.},
}

@article {pmid41935801,
year = {2026},
author = {Kong, L and Wu, Y and Zeng, H and Wu, R and Xu, X and Lu, Z and Zhang, W and Ma, C},
title = {The preclinical evidence and clinical translational prospects of medicarpin.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108183},
doi = {10.1016/j.phrs.2026.108183},
pmid = {41935801},
issn = {1096-1186},
abstract = {Medicarpin (MED) is an isoflavonoid compound derived from traditional Chinese medicine (TCM). Numerous preliminary experimental studies have shown that MED has significant pharmacological effects in the treatment of cancer, osteoporosis, osteoarthritis, Alzheimer's disease (AD), arthritis, and other diseases. However, the clinical application of MED has not yet been reported. Summarizing the preclinical drug research of MED is helpful for clarifying its pharmacological activities and evaluating its research prospects. In this review, we search for the preliminary experimental research of MED, encompassing pharmaceutics, pharmacodynamics, pharmacology, pharmacokinetics, clinical studies, and toxicology. A comprehensive review of the chemical synthesis and biosynthesis, biological activities, mechanisms, bioavailability, and clinical research of MED is conducted to systematically evaluate its safety, efficacy, and druggability. Ultimately, our work promotes the understanding of MED and facilitates its clinical translation and application.},
}

@article {pmid41936348,
year = {2026},
author = {Shimasaki, R and Kurihara, M and Bannai, T and Hatano, K and Suzuki, F and Tokumaru, AM and Ishii, K and Ihara, R and Iwata, A},
title = {Amyloid-related imaging abnormalities in Japanese patients with Alzheimer's disease treated with Lecanemab: A real-world study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100562},
doi = {10.1016/j.tjpad.2026.100562},
pmid = {41936348},
issn = {2426-0266},
abstract = {BACKGROUND: Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice.

OBJECTIVES: This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting.

DESIGN: A real-world observational study with a follow-up period of up to 18 months.

SETTING: A single center in Japan.

PARTICIPANTS: We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion.

MEASUREMENTS: Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation.

RESULTS: The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8).

CONCLUSION: In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy.},
}

@article {pmid41933174,
year = {2026},
author = {Cummings, JL and Agadjanyan, MG and Barry, M and Corey, L and Doody, R and Hendrix, S and Mattke, S and Mattsson-Carlgren, N and McDade, E and Menetski, JP and Mohs, RC and Partrick, KA and Petrovsky, N and Selkoe, DJ and Silva, D and Sperling, RA and Tiede, B and Vradenburg, G},
title = {Target product profiles for treatments to delay or prevent symptomatic Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41933174},
issn = {1546-170X},
abstract = {Despite advances in understanding the mechanisms, risk factors and treatment strategies for Alzheimer's disease (AD), no approved therapies exist to prevent or delay onset in at-risk individuals or those with elevated biomarkers who do not yet show symptoms. Multiple candidate interventions are now being evaluated in clinical trials in these settings, raising key questions around which populations are most appropriate and what criteria should guide regulatory and clinical decision-making. Data are expected within 1-2 years, underscoring the need for stakeholder alignment on clinically meaningful and acceptable characteristics of preventative therapies or other products. To address this need, the Global CEO Initiative on Alzheimer's Disease convened an international group of experts to develop target product profiles for therapies designed to delay or prevent the onset of clinical symptoms in AD. These target product profiles outline minimum and preferred characteristics, including intended use, target populations, safety expectations and efficacy benchmarks. This effort provides a foundational framework to accelerate therapeutic development and guide researchers, regulators and patients in the evaluation of emerging therapies for preventing symptomatic AD.},
}

@article {pmid41933339,
year = {2026},
author = {Huang, N and Hong, R and Cui, X and Cao, L and Shi, L and Chen, B and Su, Y and Xu, X and Hua, C and Ying, T},
title = {Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04297-2},
pmid = {41933339},
issn = {1477-3155},
support = {82272018//the National Natural Science Foundation of China/ ; ynnkxzd202404//Shanghai Sixth People's Hospital Institutional Brain Science and Brain-Inspired Research Project/ ; },
abstract = {BACKGROUND: Impaired clearance of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). Although histone deacetylase (HDAC) inhibitors show therapeutic potential, their clinical translation for AD is hampered by poor blood brain barrier (BBB) penetration and an incomplete understanding of their mechanism in Aβ clearance. Here, angiopep2-conjugated nanoparticles (SAHA@LIPO-ANG2) for efficient BBB translocation and delivery of the HDAC inhibitor vorinostat (SAHA) was developed and its underlying mechanisms were validated.

RESULTS: Our result demonstrates that SAHA@LIPO-ANG2 potently inhibits HDAC4 nuclear translocation, which was identified as a key upstream event responsible for the transcriptional repression of sodium-hydrogen exchanger 6 (NHE6). Restoration of NHE6 expression rectifies endosomal hyperacidification, thereby rescuing the trafficking and plasma membrane expression of the Aβ clearance receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Furthermore, this HDAC4-NHE6-pH axis modulates the neuroimmune microenvironment to enhance Aβ clearance through multiple synergistic mechanisms: it upregulates phagocytic receptors and recruit microglial to phagocytize Aβ plaques, while concurrently reactivating autophagy-lysosomal function in astrocytes by increasing LAMP2 expression. Consequently, treatment with SAHA@LIPO-ANG2 in 5xFAD mice significantly reduced Aβ burden, suppressed neuroinflammation, rescued synaptic loss, and ultimately reversed cognitive deficits.

CONCLUSIONS: Our study not only elucidates a HDAC4-NHE6-pH regulatory axis in AD pathogenesis but also establishes a multifaceted nanotherapeutic strategy for restoring Aβ homeostasis. Our findings may provide therapeutic strategies for treating amyloid-related diseases.},
}

@article {pmid41933799,
year = {2026},
author = {Huang, Q and Lv, Y and Ye, X and Xia, X and Chen, Y and Wang, X and Tong, F and Yang, W and Bozorov, K and Shevtsov, M and Li, H and Gao, H and Ye, B},
title = {Engineered microglial membrane-coated polydopamine-based nanomedicine for precise treatment of Alzheimer's disease.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114896},
doi = {10.1016/j.jconrel.2026.114896},
pmid = {41933799},
issn = {1873-4995},
abstract = {Multimodal treatment for Alzheimer's disease (AD) is a pivotal option because of its complex pathogenesis. The major challenge of pharmacotherapies is effective drug delivery to the diseased brain and reduction of associated toxicity. Here, we propose a dual-target nanomedicine (PDA@R@M/K) for the management of AD by coating engineered microglial cell membrane (M/K) onto polydopamine (PDA) cores encapsulated with rivastigmine. M/K conferred nanoparticles (NPs) with reduced circulation clearance, pathological blood-brain barrier recognition, and enhanced brain inflammation chemotaxis. PDA cores not only acted as potent ROS scavengers to alleviate neuroinflammation but also piggybacked rivastigmine and implemented responsive release. After applying PDA@R@M/K in preclinical transgenic mouse models, amyloid plaque deposition, neurologic changes, and cognitive decline were largely rescued. These results provide the possibility of directly using NPs as therapeutics rather than merely as nanocarriers, and demonstrate the feasibility of engineered microglia membrane-coated NPs to improve the pharmacokinetics and efficacy of anti-AD drugs.},
}

@article {pmid41933986,
year = {2026},
author = {Patel, S and Reisch, A and Narapareddy, BR},
title = {Frontal variant Alzheimer's disease presenting as late-onset psychiatric illness: A case series highlighting diagnostic challenges on inpatient psychiatric units.},
journal = {Journal of the National Medical Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jnma.2026.03.005},
pmid = {41933986},
issn = {1943-4693},
abstract = {BACKGROUND: Neurocognitive disorders are classified within psychiatric nosology and may present with prominent behavioral, mood, or psychotic symptoms that resemble other psychiatric illnesses. This overlap can lead to diagnostic ambiguity, delayed recognition of neurodegeneration, and unnecessary or harmful treatments. Frontal variant Alzheimer's disease (fvAD) is particularly prone to misdiagnosis because behavioral symptoms may precede memory impairment.

OBJECTIVE: To describe three cases of fvAD initially diagnosed as other psychiatric illnesses and to highlight strategies for improving diagnostic accuracy on inpatient psychiatric units.

METHODS: Three adults hospitalized for late-onset psychiatric syndromes refractory to standard treatment underwent systematic cognitive assessment, neuropsychological evaluation, and neuroimaging. Diagnoses were subsequently clarified as fvAD.

RESULTS: All patients initially received antipsychotic medications; two developed extrapyramidal symptoms. Cognitive assessment, collateral history, neuropsychological testing, and FDG-PET/MRI demonstrated patterns consistent with fvAD, enabling diagnostic clarification, discontinuation of ineffective treatments, and engagement of appropriate dementia care.

CONCLUSION: Late-onset psychiatric syndromes resistant to treatment may represent early manifestations of neurocognitive disorders rather than other psychiatric conditions. Systematic assessment facilitates accurate diagnosis, reduces unnecessary interventions, and supports timely referral to multidisciplinary dementia care.},
}

@article {pmid41934898,
year = {2026},
author = {Zhong, J and He, X and Yang, H and Zhang, J and Liu, J and Yang, J and Dong, X},
title = {Icariin, astragaloside IV and puerarin mixture salvages synaptic loss by enhancing mitochondrial biogenesis: A multi-target strategy for Alzheimer's disease therapy.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {198},
number = {},
pages = {119320},
doi = {10.1016/j.biopha.2026.119320},
pmid = {41934898},
issn = {1950-6007},
abstract = {OBJECTIVE: This study aimed to elucidate the potential mechanism by which the Icariin, astragaloside IV and puerarin (Ying-Huang-Ge, YHG) mixture regulates mitochondrial-synaptic homeostasis in Alzheimer's disease (AD) MOD mice through the Glycogen Synthase Kinase-3β (GSK-3β)/Peroxisome Proliferator-Activated Receptor γ Coactivator-1α (PGC-1α) signaling axis.

METHODS: Thirty 5-month-old male APP/PS1 mice were randomly divided into the MOD group, the YHG treatment group (YHG), and the Donepezil treatment group (DNP) (n = 10 per group). Ten age-matched male C57BL/6 J mice served as the CON group. Following two months of continuous administration, cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. Dendritic spine density in the hippocampal CA1 region was evaluated via Golgi staining, and ultrastructural changes were examined using transmission electron microscopy (TEM). Hippocampal levels of adenosine triphosphate (ATP), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured using biochemical assay kits. Protein expression levels of GSK-3β, p-GSK-3β (Ser9), PGC-1α, mitochondrial functional proteins (NRF-1, TFAM), and synaptic plasticity-related proteins (PSD95, SYN) were determined by Western blot.

RESULTS: Compared with the CON group, the MOD group exhibited significantly impaired learning and memory capabilities, reduced dendritic spine density in the hippocampal CA1 region, and disrupted synaptic ultrastructure. Mitochondria displayed pathological changes, including swelling and vacuolization. Furthermore, ATP and SOD levels were significantly decreased, while MDA content was elevated. Western blot analysis revealed increased total GSK-3β expression and significantly decreased expression of p-GSK-3β (Ser9), PGC-1α, downstream mitochondrial biogenesis proteins (NRF-1, TFAM), and synaptic proteins (PSD95, SYN). Intervention with YHG significantly ameliorated these cognitive deficits, mitigated pathological damage to mitochondria and synapses, and reversed the abnormal molecular expression profiles.

CONCLUSION: The YHG ameliorates cognitive dysfunction and attenuates synaptic impairment in APP/PS1 mice. The underlying mechanism may involve the inhibition of GSK-3β activity, which subsequently activates PGC-1α-mediated mitochondrial biogenesis, enhances mitochondrial quality, and mitigates oxidative stress, ultimately leading to the restoration of synaptic structural integrity.},
}

@article {pmid41926304,
year = {2026},
author = {Senwar, KR and Dhillon, A and Yadav, M},
title = {Small Molecule Inhibitors Targeting Pathogenic Protein Aggregation in Neurodegenerative Diseases: Medicinal Chemistry and Mechanistic Insights.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266439510260223082224},
pmid = {41926304},
issn = {1873-4294},
abstract = {A hallmark of Neurodegenerative Diseases (NDs) is protein misfolding, aggregation, and accumulation in specific brain regions. The accumulation of insoluble, misfolded protein aggregates is usually referred to as amyloid formation. This process leads to cellular dysfunction, destruction of neurons, loss of neuronal connections in specific brain areas, and brain damage. Despite the involvement of distinct pathogenic proteins, the underlying mechanisms of misfolding and aggregate formation are remarkably similar across various NDs. In this review, we present a comprehensive overview of the medicinal chemistry and mechanistic insights into phytochemicals and synthetic small molecules with potential for the treatment of neurodegenerative disorders. Various small molecules have been reported to have therapeutic effects by inhibiting the misfolding, aggregation, and accumulation of pathogenic proteins, such as amyloid-β, tau, and α- synuclein. This review mainly covers natural product-derived small molecules, notably polyphenols (including flavonoids and non-flavonoid polyphenols), as well as other phytochemical classes, such as quinones and alkaloids, along with their possible mechanisms of action. In addition, synthetic small molecules, osmolytes, metal chelators, and repurposed drugs for neurodegenerative disorders are thoroughly discussed.},
}

@article {pmid41926844,
year = {2026},
author = {Beyrer, J and Sheff, Z and Payakachat, N and Chandler, JM and Chen, YF and Kubisiak, J and Lee, A and Holdridge, KC and Yaari, R and Aisen, P and Rafii, MS and Sperling, RA and , },
title = {Increase in healthcare utilization and Medicare payment with progression of preclinical Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100547},
doi = {10.1016/j.tjpad.2026.100547},
pmid = {41926844},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) begins with the preclinical stage (Stages 1 and 2) where individuals are cognitively unimpaired but have AD pathology. Healthcare utilization and medical cost of cognitively unimpaired (preclinical) AD have not been previously evaluated.

OBJECTIVES: To describe healthcare resource utilization (HRU) and Medicare payments among cognitively unimpaired individuals with and without elevated amyloid and to evaluate the association of AD progression with HRU and Medicare payments.

DESIGN: Retrospective cohort analysis of the randomized controlled trial (Anti-Amyloid Treatment in Asymptomatic AD [A4]) and companion observational study (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN]) linked with Medicare.

SETTING: Clinical trials sites in the United States PARTICIPANTS: 246 cparticipants with cognitively unimpaired AD in A4 and 121 amyloid-negative participants in LEARN Medicare cohorts.

MEASUREMENTS: Measures from Medicare claims included medical conditions (diagnosis codes), HRU (inpatient, emergency room, outpatient, professional, skilled nursing facility, home health), and Medicare payments. AD progression (or cognitive or functional decline) was measured using Clinical Dementia Rating Scale-Global Score (CDR-GS) in A4/LEARN and diagnosis codes for cognitive impairment, AD, and JEN Frailty Index (JFI) of ≥6 (high frailty) in Medicare data.

RESULTS: HRU and payments were overall similar between A4 and LEARN Medicare. Claims indicators suggesting AD progression in A4 Medicare were associated with higher inpatient, outpatient, emergency room, and home health utilization (any utilization) and increased number of inpatient stays. Payments were significantly greater in A4 Medicare with AD progression vs without progression: 45% payment increase for cognitive impairment (p=0.035) with a mean incremental cost of $140 per person per month (PPPM) (95% confidence interval [CI] $125-$155), 66% payment increase for AD (p=0.011) with a mean incremental cost of $207 PPPM (95% CI $188-$226), and 103% payment increase for high frailty (p<0.001) with a mean incremental cost of $303 PPPM (95% CI $283-$323).

CONCLUSIONS: Overall, individuals with cognitively unimpaired AD in A4 Medicare did not have increased utilization and payments vs LEARN. HRU and payments were significantly greater in A4 Medicare participants with AD progression indicators in claims vs those without progression. These results highlight the need for additional research on both health and economic impacts of progression in a real-world (routine care) cohort of individuals with cognitively unimpaired AD and the potential cost savings associated with effective therapy that delays AD progression in cognitively unimpaired AD.

NCT02008357, NCT02488720.},
}

@article {pmid41928631,
year = {2026},
author = {Huang, Y and Zhu, X and Yang, S and Zhang, Y and Tan, Z and Han, S},
title = {Digital Technology in Cognitive Decline: Bibliometric and Visualization Study.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050420571260126043841},
pmid = {41928631},
issn = {1875-5828},
abstract = {With an increasing prevalence of cognitive decline diseases around the world, digital technologies are becoming an important tool for their prevention, diagnosis, and treatment. In this study, we present a comprehensive bibliometric study on the application of these digital technologies in the field of cognitive decline. This study intends to examine the trends of development and research hotspots of digital technology in cognitive decline field by bibliometric analysis. The literature has been analyzed in a systematic way. Bibliometrix R-package and VOSviewer were used to investigate publication tendency, country contribution, scholar influence, and research hotspots. A total of 1661 articles from 2006 to 2023 were analyzed. Results show an exponential increase in the number of annual publications on digital technologies applications and cognitive decline. The top journals, by volume of publication, are Alzheimer's & Dementia, the Journal of Alzheimer's Disease, and Neurology. The US is the dominant contributor of literature to this field, and the key countries for author impact include Greece, the USA, and Italy. Current research hotspots include virtual reality, machine learning, and artificial intelligence, based on analysis of keywords. This study characterizes the overall research progress and reveals research hotspots, trends, and the collaboration status among countries, on the utilization of digital technologies for cognitive decline. Moving forward, we call on researchers to increase developed/developing countries collaboration, to further implement digital technologies to counteract the public health burden of cognitive decline.},
}

@article {pmid41928975,
year = {2026},
author = {Ma, X and Koppelmans, V and Akcicek, H and Akcicek, EY and Shen, J and Chen, L and Balu, N and Yuan, C and King, JB},
title = {SNAP MRI Reveals Association Between Distal Cerebral Arterial Flow and Cognitive Function in an Aging Population.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.21.713392},
pmid = {41928975},
issn = {2692-8205},
abstract = {OBJECTIVE: Impaired blood flow has recently been recognized as a critical contributor to cognitive impairment and dementia. It was reported that cerebral distal arterial flow measured from Simultaneous Non-contrast Angiography and Intraplaque Hemorrhage (SNAP) MRI is associated with post-treatment cognitive function improvement in carotid atherosclerosis patients. In this study, we aim to evaluate the value of SNAP-based measurements in assessing cerebrovascular function in an aging population.

MATERIALS AND METHODS: Neurovascular MRI data were collected on 36 aging participants (22 cognitively unimpaired and 14 impaired; 9 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD)). Neurovascular MRI measurements, including white matter hyperintensities (WMH) volumes, cerebral blood flow (CBF), and SNAP-based distal cerebral arterial flow (dCAF) index, were quantified. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

RESULTS: Significant differences in the dCAF index were observed between cognitively unimpaired and impaired groups, and the dCAF index was significantly correlated with the RBANS total score. While CBF was significantly associated with dCAF index, there is no significant correlation of CBF or WMH with the RBANS score in this population.

CONCLUSION: Our findings suggest that the dCAF measured with SNAP MRI is valuable for evaluating the cognition-related cerebrovascular condition in an aging population.},
}

@article {pmid41929577,
year = {2026},
author = {Kandasamy, K and Narasimhamoorthi, SP and Arulselvan, P and Jaganathan, D},
title = {Protective effects of the natural polyphenol garcinol from Garcinia indica mitigates aluminium chloride-induced Alzheimer's-like neurodegeneration in Drosophila melanogaster.},
journal = {3 Biotech},
volume = {16},
number = {4},
pages = {154},
pmid = {41929577},
issn = {2190-572X},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects millions of people affected in worldwide. Natural resources such as medicinal plants have been utilized for the treatment of various memory disorders like amnesia, dementia, Alzheimer's, and Parkinson's for a long time. This study aimed to investigate plants with therapeutic bioactivities for a range of scientific investigations focused on the neuroprotective effects of garcinol from Garcinia indica against the Aluminium chloride (AlCl3)-induced AD in the Drosophila melanogaster model. Polar and non-polar solvents were active on the G. indica fruit rind and subjected to phytochemical investigation. Garcinol was extracted from the EtOH extract of G. indica fruit rind using TLC, column chromatography, GC-MS, UV-visible, and FT-IR. In vitro free radical scavenging effect of the EtOH extract of G. indica fruit rind was studied to determine its antioxidant properties. The effect of garcinol on the interaction and predicted binding interaction of the AD-associated enzymes Amyloid-β, Acetylcholinesterase (AChE), and β-secretase was studied by the in-silico analysis. AD condition was initiated in D. melanogaster by challenging them with AlCl3, and they were pre-treated with garcinol, which is isolated from the EtOH extract of G. indica fruit rind. The effect of garcinol on the AChE activity, oxidative stress markers, and pro-inflammatory cytokines was studied using the respective assay kits. The apoptotic proteins were studied using the RT-PCR analysis. The findings of the phytochemical analysis. In silico garcinol effectively interacts with and inhibits the intermolecular Amyloid-β, AChE, and β-secretase enzymes. AD, garcinol treatment successfully moderated the amendments in behavioural and cognitive impairments, regulated the oxidative stress markers, decreased AChE activity, and reduced the pro-inflammatory cytokine levels. The RT-PCR method proved that garcinol regulated the pro- and anti-apoptotic protein expressions in the AD-induced D. melanogaster. The findings suggested that garcinol from EEGIFR acts against AlCl3-induced AD in D. melanogaster because of its anti-inflammatory, antioxidant, and apoptosis-modulating capabilities, and it may develop as a capable therapeutic agent in treating AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04763-6.},
}

@article {pmid41929929,
year = {2025},
author = {Tang, Y and Zhuo, E and Li, P and Wang, C and Hu, X and Liu, X and Xu, G and Shen, Q},
title = {MANF improves cognitive function and attenuates neuroinflammation in APP/PS1 transgenic mice through the TLR4/MYD88/NF-κB signaling pathway.},
journal = {Journal of anesthesia and translational medicine},
volume = {4},
number = {4},
pages = {241-254},
pmid = {41929929},
issn = {2957-3912},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline, as well as pathological features such as β-amyloid (Aβ) plaque deposition, tau hyperphosphorylation, synaptic dysfunction, and neuronal loss. Growing evidence suggests that neuroinflammation, oxidative stress, and apoptosis play critical roles in the pathogenesis of AD, thereby contributing to neuronal damage and cognitive decline. Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible protein, has been shown to exert neuroprotective effects by modulating immune responses, alleviating oxidative stress, and suppressing apoptosis in various neurological disease models. These properties suggest that MANF could serve as a promising therapeutic candidate treating AD. This study investigated the therapeutic potential of MANF in improving cognitive function and ameliorating pathological changes in APP/PS1 transgenic (Tg) mice by modulating neuroinflammation and enhancing neural plasticity.

METHODS: Beginning at 10 months of age, male APP/PS1 transgenic mice received daily intraperitoneal injections of recombinant human MANF (rhMANF) at a dose of 1 μg/g for a duration of one month. Behavioral assessments, including the Morris water maze, open field, and fear conditioning tests, were conducted to evaluate cognitive function. Brain tissue was analyzed for β-amyloid (Aβ) deposition, neuroinflammation, oxidative stress, and neuronal apoptosis using immunofluorescence, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. RNA sequencing (RNA-seq) and a BV2 microglial/HT22 neuronal co-culture system were used to further elucidate the mechanisms underlying MANF's effects.

RESULTS: rhMANF treatment significantly improved cognitive function in APP/PS1 Tg mice by reducing Aβ deposition, inhibiting microglial activation, and suppressing inflammatory cytokines (TNF-α, IL-1β, and IL-6). MANF also mitigated oxidative stress, reduced neuronal apoptosis, and restored synaptic protein levels, including those of Postsynaptic density protein-95(PSD95) and synaptophysin (SYN). In vitro studies confirmed that MANF effectively counteracts Aβ1-42-induced toxicity in the BV2/HT22 co-culture system. Transcriptomic analysis identified that MANF exerts its protective effects by regulating the TLR4/MYD88/NF-κB signaling pathway, thereby reducing inflammation and promoting synaptic plasticity.

CONCLUSIONS: This study demonstrates the protective role of MANF in AD and establishes MANF as a promising therapeutic candidate for AD and aging-related neurodegenerative disorders.},
}

@article {pmid41929945,
year = {2026},
author = {Yang, Y and Meng, Y and Li, M and Xu, Z and Wu, H and Zhang, Q and Zhang, S and Kong, F and Wang, Z and Li, X and Zhu, Y},
title = {Identification of potential short-chain fatty acid biomarkers in Alzheimer's disease through bioinformatics analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261424808},
pmid = {41929945},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder. Accumulating evidence suggests that short-chain fatty acids (SCFAs) can regulate the central nervous system, thereby affecting cognitive and behavior function.

OBJECTIVE: This study aimed to investigate the association between the AD development and SCFA metabolism via bioinformatic analysis.

METHODS: Gene expression profiles were obtained from the GEO database. 1243 genes related to SCFA were screened from Genecards database. Through weighted gene co-expression network analysis (WGCNA) and differential analysis, 10 SCFA hub genes were screened. Machine learning algorithms, including support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression models, were used to identify candidate biomarkers. The CIBERSORT algorithm was utilized to evaluate the infiltration of immune cells and its relationship with the potential biomarkers. The candidate biomarker chemicals were identified in the Comparative Toxicogenomics Database as underlying targeted drugs for treating AD.

RESULTS: Five genes-EZR, SNCA, GFAP, NFKBIA, and SST-were identified as potential biomarkers for AD through LASSO and SVM-RFE analyses. These genes can also be used to predict the risk of AD and have good diagnostic effects. The candidate biomarkers are associated with plasma cells, activated dendritic cells, M1 macrophages and resting natural killer cells. Notably, valproic acid and tretinoin were found to target these candidate genes, suggesting a new treatment approach for AD.

CONCLUSIONS: This study identified EZR, SNCA, GFAP, NFKBIA, and SST as potential key SCFA-related genes associated with the progression of AD, providing new insights into the prevention and treatment of AD.},
}

@article {pmid41929949,
year = {2026},
author = {Zhang, Q and Almanie, L and Ouyang, Y and Cheng, Z and Zhang, H},
title = {From routine periodontal therapy to Alzheimer's disease early detection: A scoping review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261421629},
pmid = {41929949},
issn = {2542-4823},
abstract = {An epidemiological association has been observed between periodontitis and Alzheimer's disease (AD); however, salivary and blood assays often show low specificity. Periodontal tissues and fluids, which are routinely removed and discarded during periodontal treatment, may be collected to offer matrices useful for the early detection of AD. This study aimed to map current preclinical and clinical evidence on biomarkers measured in periodontal tissues and fluids for the early detection of AD and organize them within an AD-specificity pyramid anchored to brain-relevant endpoints. Following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews) guidance, we searched PubMed, Scopus, and Web of Science (January 1, 2015-August 31, 2025) for preclinical and clinical studies measuring AD-relevant biomarkers in periodontal matrices. The protocol was pre-registered (OSF DOI: 10.17605/OSF.IO/EDVU9; August 20, 2025). Two reviewers extracted the data, and other two independently verified them. The findings were organized using a four-tier AD-specificity pyramid. Results: Fourteen studies met the inclusion criteria. The biomarkers from the included studies were clustered into microbiome features, molecular signals, and genetic/transcriptomic findings. Evidence ranged from Tier-1 contextual inflammation/pathogens to Tier-4 core-pathology adjacency; five studies incorporated clinical/biological anchoring, with cerebrospinal fluid amyloid-β positivity providing the most brain-relevant anchor. Periodontal matrices are practicable, high-signal sources for AD-relevant biomarkers. However, translational validation linking periodontal biomarkers to brain endpoints is needed to assess the feasibility of multi-tier and chairside panels for early AD detection as part of routine periodontal care.},
}

@article {pmid41929950,
year = {2026},
author = {Lin, F and Yang, X and Xie, X and Qiu, L and Zheng, C and Zheng, X and Li, Z and Nie, B},
title = {The causal association between the new gut microbiota and Alzheimer's disease: A Mendelian randomization study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261422629},
pmid = {41929950},
issn = {2542-4823},
abstract = {BACKGROUND: There is a need for more studies to validate the role of gut microbiota in Alzheimer's disease (AD).

OBJECTIVE: This study aims to explore the causal association between new gut microbiota and AD using Mendelian randomization.

METHODS: Using genome-wide association study (GWAS) of 473 gut microbiota species and AD in IEU Open GWAS database, independent genetic loci related to gut microbiota were extracted as instrumental variables. The inverse variance weighting method was employed as the main indicator for evaluation. The stability and reliability of the results were further verified by heterogeneity test, outlier detection, horizontal pleiotropy test and leave-one-out analysis.

RESULTS: Following a thorough screening process, a total of 14 intestinal microbiota were included in the final analyses. The elevated abundance of Agathobacter, Citrobacter A, Clostridium E sporosphaeroides, Eubacterium R, Megamonas funiformis, and Pseudomonas aeruginosa can reduce the risk of AD. Higher abundance of Bifidobacterium, Holdemania massiliensis, Hydrogenophaga, Intestinimonas massiliensis, Megasphaera, Paenibacillus J, Prevotella, and Raoultella could increase the risk of AD. The MR-Egger analyses at 14 "genus" levels showed no horizontal pleiotropy and the p values were all more than 0.05. The leave-one-out analysis showed that results were relatively stable.

CONCLUSIONS: This study revealed a causal relationship between 14 specific gut microbiota and the risk of AD occurrence. Some bacteria are protective, while others increase the risk of AD. These findings are of clinical significance for the treatment and prevention strategies in clinical practice, and it also provides new perspectives for related research on the "gut-brain axis".},
}

@article {pmid41929952,
year = {2026},
author = {Huang, S and Guo, Y},
title = {Network meta-analysis of the efficacy of nine drugs for cognitive function in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261422205},
pmid = {41929952},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) remains a global challenge, and the comparative cognitive efficacy of emerging pharmacotherapies is still unclear.

OBJECTIVE: To compare and rank nine pharmacological agents against placebo in AD with respect to key cognitive outcomes using a network meta-analysis.

METHODS: We systematically searched randomized controlled trials published up to May 2025 that evaluated aducanumab, lecanemab, donanemab, gosuranemab, semorinemab, tilavonemab, zagotenemab, masupirdine, or sodium oligomannate in AD. The primary outcomes were Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog); Mini-Mental State Examination (MMSE) was a secondary outcome. Treatments were ranked using the Surface Under the Cumulative Ranking curve (SUCRA).

RESULTS: Fifteen randomized trials encompassing 33 treatment arms were included. No drug demonstrated statistically robust superiority over placebo in primary outcomes. Semorinemab and tilavonemab achieved highest SUCRA rankings, but without significant pairwise advantage. For MMSE, aducanumab showed a modest mean difference versus placebo (1.98, 95% CI 0.03-3.93), though evidence of publication bias reduced confidence.

CONCLUSIONS: Current pharmacological treatments do not consistently outperform placebo in AD. Tau-targeted antibodies (semorinemab, tilavonemab) display modest but non-significant promise, whereas aducanumab's apparent benefit is likely confounded by publication bias. Further large, rigorous randomized controlled trials and improved preclinical models are essential.},
}

@article {pmid41929955,
year = {2026},
author = {Qiu, Q and Qian, W and Zhao, W and Xie, H and Cao, L and Ye, L and , },
title = {P-tau217 and %p-tau217 exhibited superior diagnostic accuracy over other blood biomarkers in the initial assessment of individuals being diagnosed with mild cognitive impairment and Alzheimer's disease dementia.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261439687},
pmid = {41929955},
issn = {2542-4823},
abstract = {BACKGROUND: High-performance blood tests may improve diagnostic accuracy and support personalized treatment for Alzheimer's disease (AD), but validation at the time of initial clinical diagnosis remains limited.

OBJECTIVE: To assess whether plasma biomarkers can aid diagnostic decision-making at first clinical assessment, particularly as tools to triage patients for confirmatory testing in routine practice.

METHODS: We analyzed 241 cognitively normal (CN) controls, 211 patients with mild cognitive impairment (MCI), and 59 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. Plasma aliquots underwent analysis with the C2N Diagnostics PrecivityAD2[®] and Roche Diagnostics Elecsys[®] assays.

RESULTS: The AD group showed a lower Aβ42/Aβ40 ratio than the CN group (p < 0.01) and a mild decrease compared to the MCI group (p < 0.05). The AD group had significant increases in p-tau181, p-tau217, and %p-tau217 (p < 0.001) versus both MCI and CN groups. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were also significantly elevated in AD. The MCI and CN groups only differed in p-tau217 and %p-tau217 (p < 0.05). The AD versus CN AUCs for p-tau181, p-tau217, and %p-tau217 were 0.84, 0.87, and 0.87; for AD versus MCI, they were 0.79, 0.80, and 0.81. The p-tau181, p-tau217, and %p-tau217 showed a moderate correlation with the Alzheimer's Disease Assessment Scale-cognitive subscale. %p-tau217 demonstrated a strong correlation with the p-tau181/Aβ42 ratio in CSF (R = 0.72, p < 0.001).

CONCLUSIONS: In the setting of first-presentation diagnosis of clinically defined MCI and AD, p-tau217, and %p-tau217 outperformed other plasma biomarkers and may help triage patients for further confirmatory evaluation.},
}

@article {pmid41929956,
year = {2026},
author = {Rahman-Filipiak, A and Lesniak, M and Burgei, A and Sadaghiyani, S and Roberts, JS and Lichtenberg, PA and Iordan, A and Mozersky, J and Hampstead, BM},
title = {Qualitative insights into participant and care partner perspectives on research-based Alzheimer's disease biomarker testing and disclosure.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261429997},
pmid = {41929956},
issn = {2542-4823},
abstract = {BACKGROUND: There is strong desire for the return of individual results, including biomarker testing, among participants in Alzheimer's disease and related dementias (ADRD) studies. However, it is not known whether participants accurately understand the utility, limitations, benefits and risks of biomarker disclosure, nor how they weigh these factors to inform their decision to undergo testing and learn results. Furthermore, little is known about how factors like participant race or diagnosis influence a desire to learn biomarker results.

OBJECTIVE: This mixed-methods study explored how clinically and racially diverse participant-care partner dyads perceive and plan to use AD biomarker testing in the context of research studies.

METHODS: 57 participants (Age: M = 74.28 ± 5.98; Race: n = 22 Black, n = 35 White; Diagnosis: n = 23 with mild cognitive impairment; n = 34 cognitively healthy) and care partners were recruited from AD studies wherein the participant completed amyloid-β and tau positron emission tomography without receiving results. Each completed an independent interview about their perspectives on learning the participant's results.

RESULTS: Responses suggested strong interest in learning results, driven by perceived benefits (e.g., informing treatment, lifestyle changes, and social support). Risks were rarely discussed, though some respondents cited concerns about psychological burdens of a positive result. Few nuanced differences in perceived risks or benefits were observed across race and diagnosis.

CONCLUSIONS: The decision to learn the results of biomarker testing is motivated by highly varied perceived benefits and minimal consideration of risks. Testing should be preceded by individualized counseling that carefully reviews potential benefits and risks.},
}

@article {pmid41929964,
year = {2026},
author = {Zhao, X and Wu, L and Li, P},
title = {TARDBP gene mutation in a Chinese family with frontotemporal dementia: A case report and literature review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251412416},
pmid = {41929964},
issn = {2542-4823},
abstract = {BACKGROUND: Mutations in the transactive response DNA binding protein (TARDBP) have never been reported in the population of familial frontotemporal dementia (FTD) in Chinese mainland.

OBJECTIVE: This study reports for the first time a familial FTD carrying TARDBP mutations in Chinese mainland and summarizes the genetic and clinical features of TARDBP mutant families.

METHODS: Case report of comprehensive clinical, genetic and neuroimaging examinations on a 68-year-old male patient diagnosed with behavioral variant FTD (bvFTD). A literature review was also conducted and clinical and genetic features of families with TARDBP mutations were summarized.

RESULTS: We reported the bvFTD patient in Chinese with heterozygous mutation of TARDBP. Brain MRI revealed bilateral frontal and temporal atrophy, predominant in the right side. FDG-PET demonstrated frontal and temporal hypometabolism. [18]F-DPA714-PET showed focally elevated bilateral temporal tracer uptake, and [18]F-MNI-1126-PET revealed a reduction in synaptic uptake throughout the brain, especially in the bilateral temporal lobes. In the literature, we found 68 patients from 24 families with 6 different TARDBP mutations in an exon 6. Nine patients presented with symmetrical atrophy involving the frontal, temporal, and parietal lobes, 11 with asymmetrical atrophy, and 5 without atrophy. More than 60.3% of the patients had an onset age earlier than 65 years old and there was a predominance of men.

CONCLUSIONS: Our discovery confirmed a pedigree of FTD families and expanded the pedigree mutation spectrum of TARDBP in China. The establishment between phenotype and genotype will aid the diagnosis and treatment of FTD.},
}

@article {pmid41929976,
year = {2026},
author = {Parmar, H and Walden, E and , },
title = {Towards practical application of deep learning in diagnosis of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261415808},
pmid = {41929976},
issn = {2542-4823},
abstract = {BACKGROUND: Accurate diagnosis of Alzheimer's disease (AD) is both challenging and time consuming. With a systematic approach to diagnosis, steps can be taken toward improved treatment and prevention of the disease.

OBJECTIVE: This study explores the practical application of deep learning models for the diagnosis of AD across different disease stages.

METHODS: Due to computational complexity, long training times, and limited availability of labeled datasets, full brain three-dimensional (3D) convolutional neural networks (CNNs) are not commonly used, and many studies rely on two-dimensional (2D) variants. In this work, full brain 3D versions of well-known 2D CNN architectures were designed, trained, and tested for the diagnosis of multiple stages of AD. More than 1500 full brain volumes were used for model training and evaluation.

RESULTS: The proposed deep learning approach demonstrated good performance in differentiating various stages of AD. In addition to classification, the models were able to extract discriminative features relevant to disease stage. These features aligned with meaningful anatomical landmarks that are currently considered important for AD identification by clinical experts. An ensemble of all algorithms was also evaluated and achieved superior performance compared to individual models, with a maximum classification accuracy of 87.4%.

CONCLUSIONS: The trained 3D CNNs and their ensemble show strong potential for assisting in the diagnosis of AD. These models may be incorporated into clinical software tools to support physicians and radiologists in improved diagnostic decision making.},
}

@article {pmid41929977,
year = {2026},
author = {Kasuga, K and Yuzawa, C and Nakamura, K and Shimizu, Y and Hara, N and Ikeuchi, T and Sekijima, Y},
title = {A novel PSEN2 missense variant in a Japanese woman with hereditary Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261424532},
pmid = {41929977},
issn = {2542-4823},
abstract = {Hereditary Alzheimer's disease (hAD) and PSEN2 variants are rare, and the benefit of anti-amyloid β-directed monoclonal antibody (mAb) therapy is unknown. We encountered a 51-year-old Japanese woman with PSEN2-associated hAD. A molecular diagnosis revealed a novel uniallelic missense variant (NM_000447:c.356T > G, p.Leu119Arg) in PSEN2. Intravenous mAb therapy was initiated at age 50, and serial amyloid positron emission tomography showed intense Pittsburgh compound B accumulation and a reduction in amyloid-β deposits in the cerebral cortex after 6 months. Our results suggest that treatment with mAbs has the potential to reduce amyloid deposits in the brain, even in patients with symptomatic hAD.},
}

@article {pmid41929981,
year = {2026},
author = {Zupanic, E and Stegnar, G and Rakuša, M and Rus Prelog, P and Švab, I and Gregoric Kramberger, M},
title = {Estimates of current capacity for diagnosing and implementation of new treatment Alzheimer's disease in Slovenia.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261424524},
pmid = {41929981},
issn = {2542-4823},
abstract = {BACKGROUND: The limited efficacy of current symptomatic treatments for Alzheimer's disease (AD) leads many patients to forgo medical help. However, new disease-modifying treatments (DMTs), such as donanemab and lecanemab, show potential to change this.

OBJECTIVE: To model the impact of these treatments on Slovenia's healthcare system by analyzing patient flow under both current and enhanced capacities, assuming DMT availability.

METHODS: The study estimates 76,923 potential DMT candidates aged 65 years and older with mild cognitive impairment or mild AD. Using data from Slovenia's three specialized centers for cognitive disorders, a Markov model simulated five five-year scenarios: baseline, real-life, real-life with capacity enhancement, biomarker integration, and biomarker integration with capacity enhancement.

RESULTS: Waiting times for specialist evaluation would increase from the current 3-12 months to 1.8 years. The primary bottleneck is lumbar puncture with cerebrospinal fluid (CSF) analysis, during which 64% of patients would become ineligible for DMT. The shortest waiting time to receive DMT occurs in the biomarker integration with capacity enhancement scenario, at 4 years, reducing ineligibility to 7%.

CONCLUSIONS: Current specialized outpatient facilities are limited, causing significant bottlenecks, especially in CSF analysis. Severe waiting times under current capacities mean many patients would progress to moderate or severe dementia or die before receiving treatment. Plasma biomarkers offer a promising triage approach to guide patients toward lumbar puncture or other confirmatory diagnostics, potentially easing this critical bottleneck. Substantial infrastructure and workforce improvements are essential to ensure timely and equitable access to DMTs in Slovenia.},
}

@article {pmid41929983,
year = {2026},
author = {Paez, K and Kopachik, C and Yilmaz, A and Vishweswaraiah, S and Ashrafi, N and Saiyed, N and Monacelli, N and Kerseviciute, I and Gordevicius, J and Ruff, S and Pai, A and Khaled, I and Maddens, ME and Graham, SF},
title = {Unraveling the impact of common medications on biomarker patterns in Alzheimer's disease and mild cognitive impairment.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251387281},
pmid = {41929983},
issn = {2542-4823},
abstract = {BACKGROUND: The aging global population faces significant challenges from Alzheimer's disease (AD). Metabolomics offers a non-invasive, cost-effective diagnostic alternative. Researchers identified significant variations in the level of salivary and urinary metabolites between AD patients and cognitively healthy controls. However, it's unclear whether differences in metabolites between AD patients and healthy controls are due to the disease or medications.

OBJECTIVE: This study aims to investigate the impact of common AD medications (cholinesterase inhibitors) and hypertension medications (ARBs) on the AD patient metabolome.

METHODS: A retrospective metabolomics analysis was conducted to elucidate whether observed metabolic perturbations were attributable to AD pathology or polypharmacy, with a specific focus on cholinesterase inhibitors and ARBs.

RESULTS: Linear models revealed that cholinesterase inhibitors did not significantly modulate potential urinary and salivary biomarkers for AD. However, these inhibitors were associated with significant changes in urinary metabolite concentrations, including increased isovaleric acid and L-leucine and decreased formate and L-histidine (q = 0.027 for all). Analysis of ARB treatment revealed significantly reduced urinary tryptophan levels (q = 0.001) in AD patients and increased salivary acetone and isopropyl alcohol concentrations (q = 0.028) across all groups. Further analysis of saliva metabolite ratios revealed notable differences in asymmetric arginine methylation between the AD group and the control group (q = 0.021). Additionally, variations in citrate synthesis were observed between the mild cognitive impairment group and the control group on ARBs (q = 0.024).

CONCLUSIONS: Our research confirms that distinct biomarker profiles characteristic of AD remain present regardless of cholinesterase inhibitor and ARB treatment, providing a foundation for future clinical studies and therapeutic development by providing better diagnostic tools.},
}

@article {pmid41930591,
year = {2026},
author = {Qin, J and Xu, X and Zou, Y},
title = {Herpes zoster, antiviral therapy, and Alzheimer's disease: Turning association into an actionable prevention pathway.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438524},
doi = {10.1177/13872877261438524},
pmid = {41930591},
issn = {1875-8908},
abstract = {Yang and Jiang synthesize evidence linking varicella-zoster virus exposure to Alzheimer's disease risk and lay out a clinically intuitive pathway from infection to intervention, spanning antiviral treatment and herpes zoster vaccination. The review is timely because it highlights potentially modifiable touchpoints in routine care for older adults. Building on their work, this commentary raises one pragmatic question: what additional evidence would most efficiently translate these associations into targeted, implementable prevention strategies-clarifying when risk is most actionable, which intervention features matter most, and which subgroups may benefit most?},
}

@article {pmid41930592,
year = {2026},
author = {Vijverberg, EGB and Scharre, DW and Woodward, M and Catalano, S and Hamby, ME and Grundman, M and Morgan, RE and Iaci, J and Devins, T and Caggiano, AO},
title = {Randomized, double-blind study of zervimesine in mild to moderate Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261437145},
doi = {10.1177/13872877261437145},
pmid = {41930592},
issn = {1875-8908},
abstract = {BackgroundZervimesine (CT1812) is a first-in-class, brain-penetrant sigma-2 receptor ligand that prevents binding and displaces Aβ42 oligomers from receptors on neuronal synapses.ObjectiveThis study evaluated the safety and efficacy of zervimesine in mild to moderate Alzheimer's disease (AD).MethodsThis was a Phase 2, randomized, double-blind, placebo-controlled study. Participants were randomized to zervimesine 100 mg or 300 mg or placebo. In addition to ADAS-Cog11, outcomes were evaluated from baseline plasma p-tau217 in prespecified subgroups.ResultsOf 153 adults randomized, 150 were included in the mITT population. Adverse events occurred in 70.6% with zervimesine 100 mg, 82.4% with zervimesine 300 mg, and 78.0% with placebo. At Day 182, the ADAS-Cog 11 increased from baseline (indicating a decline in cognitive function) with the LS mean (SE) change of 2.69 (0.81) points in the placebo group versus 1.66 (0.60) points in the pooled zervimesine group [δ = -1.03 (-3.01, 0.96), p = 0.310]. For participants with baseline plasma p-tau217 levels below the median (1.0 pg/mL), the pooled zervimesine group showed greater improvement on the ADAS-Cog 11 at Day 182 relative to placebo (δ = -2.66; p = 0.080).ConclusionsThis phase 2 study indicated that zervimesine was safe and well tolerated and showed consistently favorable numerical treatment differences versus placebo. More robust treatment differences were observed in the below median baseline plasma p-tau217 group suggesting potentially greater efficacy of zervimesine in less advanced AD. These results support larger pivotal trials with zervimesine.Registered at clinicaltrials.gov: NCT03507790.},
}

@article {pmid41930760,
year = {2026},
author = {Patel, S and Sood, R and Shrivastava, S and Jeengar, MK},
title = {Neuroprotective Mechanisms of Erucin: Therapeutic Pathways in Neurodegenerative Disorders.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X385491251208144807},
pmid = {41930760},
issn = {1875-6190},
abstract = {Neurodegenerative Disorders (NDDs), including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and other less prevalent conditions, represent a growing challenge in medical science due to their progressive nature and the absence of curative treatments. Cruciferous vegetables, such as those from the Brassicaceae family and other species in the Brassicales order, have been reported to offer potential benefits for treating and preventing NDDs. Their neuroprotective effects have been attributed to secondary metabolites, glucosinolates (GLs), and their hydrolytic products, isothiocyanates (ITCs). One of these ITCs is Erucin (ERU), chemically known as 4-isothiocyanatobutane, which is a specific type of ITC. ERU is the isothiocyanate derivative of erucic acid and is structurally related to sulforaphane (SFN), another well-known ITC. This review aims to synthesize current scientific knowledge on ERU's mechanisms of action in neurodegeneration, highlighting preclinical evidence supporting its neuroprotective effects in diseases such as AD and PD, and suggesting its potential as a treatment strategy for NDDs. Preliminary studies suggest that ERU may confer neuroprotection through antioxidative stress pathways, modulation of neuroinflammatory responses, and upregulation of neurotrophic factors. This article discusses ERU's chemical properties, pharmacokinetics, and observed impacts on neurodegenerative models, suggesting potential therapeutic pathways it may influence, thereby highlighting its promise as a future component of neuroprotective strategies against NDDs.},
}

@article {pmid41930762,
year = {2026},
author = {Singh, A and Mazumder, A and Das, S and Kumar, R and Kanda, A},
title = {Synergistic Anti-dementia Effects of Symplocos racemosa Nanoemulsion: Isolation, Molecular Docking, and In Vivo Evaluation.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026421409260119050357},
pmid = {41930762},
issn = {1875-5739},
abstract = {INTRODUCTION: Dementia, marked by a decline in mental abilities like memory that interferes with daily life, is primarily caused by Alzheimer's Disease (AD). Symplocos racemosa, rich in acetyl oleanolic acid, serves as a neuroprotective agent by lowering amyloid β levels in the brain. This study aims to develop a nanoemulsion for the targeted delivery of S. racemosa phytoconstituents to enhance therapeutic efficacy against dementia. The study also aims to find out the mechanism of the responsible molecules via molecular docking studies.

METHODS: S. racemosa bark was ultrasonically extracted with methanol and ethyl acetate, yielding six phytoconstituents: ellagic acid, betulinic acid, acetyl oleanolic acid, salireposide (from methanol), oleanolic acid, symlocoside (from ethyl acetate), isolated by column chromatography. Molecular docking against AChE and BACE-1 was conducted using CB Dock-2. A chitosan- based nanoemulsion containing all six compounds was prepared to enhance brain delivery and was physically characterized. All isolated phytoconstituents and nanoemulsions were evaluated for their in vitro enzyme inhibition (AChE and BACE-1) potential. Its anti-dementia efficacy was evaluated in scopolamine-induced rodent models using Hebb-Williams and Elevated Plus Maze tests, complemented by histopathological analysis of the brain cortex to assess therapeutic effects.

RESULTS: Docking studies showed acetyl oleanolic acid had stronger binding to BACE-1 and AChE than donepezil. This was further supported by an in vitro enzyme inhibition assay. Nanoemulsion at 200 and 400 mg/kg significantly reduced the time taken by memory-impaired mice to complete the Hebb-Williams Maze and transfer latency in the Elevated Plus Maze. Histopathological analysis showed a significant recovery of cortical damage. This indicates that the nanoemulsion has strong potential for the treatment of Alzheimer 's-related neurodegeneration.

DISCUSSION: The neuroprotective action of S. racemosa nanoemulsion (SRMN) is attributed to the large-scale presence of its phytoconstituents, which reportedly exhibit a better binding affinity and inhibitory action against AChE and BACE-1 than donepezil. Additionally, the nanoemulsion enhanced bioavailability, stability, and blood-brain barrier penetration, which in turn improved therapeutic outcomes. From behavioral and histological studies, we observed that SRMN performed well in terms of memory improvement and cortical protection, suggesting that it is a very good multi-target approach for dementia.

CONCLUSION: The prepared nanoemulsion from S. racemosa's isolated phytoconstituents is reported to exhibit synergistic action, thereby effectively managing dementia through BACE-1 and AChE inhibition.},
}

@article {pmid41930767,
year = {2026},
author = {Parashar, AK and Saraogi, GK and Sethi, VA and Ahmad Yasin, HK},
title = {Nanocarriers in Alzheimer's Therapy: A Comprehensive Review on Nanoparticulate Drug Delivery Systems.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026435071260129105648},
pmid = {41930767},
issn = {1875-5739},
abstract = {INTRODUCTION: Neurodegenerative disorders, particularly Alzheimer's Disease (AD), pose a major global health challenge, characterized by progressive neuronal degeneration and cognitive decline. The blood-brain barrier (BBB) significantly limits the efficacy of conventional therapeutics, preventing adequate drug delivery to the central nervous system. Nanoparticulate Drug Delivery Systems (NPDDS) have emerged as a promising approach to overcome these limitations and enhance the therapeutic potential of AD interventions.

METHODS: This review comprehensively examines recent advancements in NPDDS for AD therapy. Various nanoparticle classes, including polymeric nanoparticles, solid lipid nanoparticles, gold nanoparticles, liposomes, microemulsions/nanoemulsions, dendrimers, and hydrogels, are evaluated with respect to their physicochemical characteristics, drug-loading capacities, BBBpenetrating strategies, and potential for targeted cerebral delivery. Relevant preclinical and clinical studies were analyzed to summarize the pharmacokinetic and pharmacodynamic benefits of these systems.

RESULTS: The reviewed NPDDS demonstrate enhanced drug solubility, stability, and controlled release profiles. Multiple strategies, such as surface functionalization, intranasal administration, and receptor-mediated transcytosis, facilitate BBB penetration and site-specific drug delivery. Nanocarriers improve drug accumulation at pathological sites, potentially enhancing therapeutic efficacy while reducing systemic side effects. Each nanoparticle class offers distinct advantages: polymeric and lipid-based systems provide controlled release and biocompatibility, while metallic and dendrimeric platforms offer theranostic capabilities and high drug-loading potential.

DISCUSSION: Despite their promise, challenges remain in translating NPDDS to clinical applications. Efficient and reproducible BBB crossing, potential cytotoxicity, long-term biocompatibility, and scalable manufacturing processes require further optimization. Multifunctional and hybrid nanocarriers, stimuli-responsive systems, and biomimetic designs are emerging to address these limitations. Continuous advancements in nanotechnology offer tunable physicochemical properties to tackle the complex pathogenesis of AD, enabling more precise, effective, and patient- compliant therapies.

CONCLUSION: NPDDS represent a transformative frontier in Alzheimer's disease management, offering targeted, efficient, and adaptable drug delivery solutions. Strategic development and rigorous evaluation of these systems may improve CNS bioavailability of therapeutic agents, enhance clinical outcomes, and potentially shift the paradigm in the treatment of neurodegenerative disorders. Future research should focus on overcoming translational challenges to realize the full potential of nanocarrier-based AD therapy.},
}

@article {pmid41930874,
year = {2026},
author = {Xiao, S and Han, Y and Yan, J and Wu, L and Lin, H and Yuan, C and Song, C and Ye, J},
title = {Salvianolic acid a inhibits neuroinflammation and ameliorates Alzheimer's disease pathology via the p38 MAPK/NF-κB pathway based on network pharmacology and experimental validation.},
journal = {International immunopharmacology},
volume = {178},
number = {},
pages = {116594},
doi = {10.1016/j.intimp.2026.116594},
pmid = {41930874},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) represents the most prevalent form of neurodegenerative disorder, characterized by progressive cognitive impairments and a scarcity of effective treatments. Salvianolic acid A (SalA), a natural phytochemical endowed with antioxidative, antiapoptotic, and anti-inflammatory properties, emerges as a promising therapeutic candidate for AD. This study explored the therapeutic efficacy and underlying mechanisms of SalA in mitigating AD-related pathologies. Through integrative network pharmacology, molecular docking, and pathway enrichment analysis, p38 MAPK and NF-κB were identified as potential targets of SalA in the context of AD. SalA treatment inhibited the activation of the p38 MAPK/NF-κB pathway via targeting p38 MAPK, leading to decreased levels of IL-1α and IL-1β in lipopolysaccharide (LPS)-stimulated HMC3 cells. In an in vivo 3 × Tg-AD mouse model, SalA administration ameliorated cognitive decline associated with AD, decreased tau protein hyperphosphorylation in the hippocampus and cortex, and reduced amyloid-β (Aβ) accumulation and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) levels. Furthermore, SalA attenuated the activation of the p38 MAPK/NF-κB pathway and the expression of related inflammatory cytokines in the brains of 3 × Tg-AD mice. In conclusion, this study elucidates the promising ameliorative effects of SalA on improving AD pathology, primarily through the modulation of the p38 MAPK/NF-κB signaling pathway.},
}

@article {pmid41931967,
year = {2026},
author = {Sun, X and Xi, Y and Chen, Y and Zhou, J and Ni, J and Ding, Y and Zhang, H},
title = {Dysfunctional microglia-targeted nanoscavenger synergistically accelerates Aβ clearance and inhibits inflammatory cascade.},
journal = {Biomaterials},
volume = {333},
number = {},
pages = {124163},
doi = {10.1016/j.biomaterials.2026.124163},
pmid = {41931967},
issn = {1878-5905},
abstract = {Amyloid-β (Aβ) clearance holds promise in Alzheimer's disease (AD) treatment, but the clinical application is limited by poor clearance efficacy and microglial inflammatory cascade caused by overloaded Aβ degradation. In this study, a polymeric lipoprotein-curcumin nanoscavenger (CP/[Man]Disc-Cur) with dysfunctional microglia-specific targeting capability is designed to synergistically promote Aβ clearance and inhibit microglial inflammatory cascade. For preparation, curcumin is post-encapsulated into mannose-modified Disc ([Man]Disc-Cur), followed by assembly with chitosan derivatives (CP) to obtain CP/[Man]Disc-Cur. After intranasal administration and triggered by the nasal acidic microenvironment, CP/[Man]Disc-Cur is depolymerized into [Man]Disc-Cur and protonated CP that adheres to reversibly open the tight junctions, promoting [Man]Disc-Cur penetration into the brain via the olfactory pathway. Thereafter, [Man]Disc-Cur captures Aβ oligomer with a high binding affinity (KD = 5.90 × 10[-8] M) and selectively targets dysfunctional microglia where Aβ catabolism is accelerated with inflammation inhibition by curcumin. After nasal treatment of CP/[Man]Disc-Cur for 4 weeks, Aβ burden, microglial inflammation, and memory deficits of APPswe/PS1dE9 transgenic AD mice are significantly attenuated without the obvious side effects. Collectively, this study provides a promising strategy for synergistically improving Aβ clearance and inhibiting microglial inflammatory cascade for enhanced AD treatment.},
}

@article {pmid41931990,
year = {2026},
author = {Gao, J and Yi, Y and Ran, W and Cheng, Y and Deng, W and Duan, S and Shi, F and Wei, Y and Zhang, Y and Gong, Q},
title = {Targeting astrocytic Nrf2 by Trilobatin alleviates lipopolysaccharide-induced depressive-like behaviors and cognitive impairment in mice: Mechanistic insights into gut microbiota and metabolites modulation.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158118},
doi = {10.1016/j.phymed.2026.158118},
pmid = {41931990},
issn = {1618-095X},
abstract = {BACKGROUND: Clinical and preclinical evidence links major depressive disorder (MDD) and Alzheimer's disease (AD), suggesting MDD treatment could prevent some AD. Dysfunction within the microbiota-gut-brain axis contributes to MDD and AD pathogenesis via dysregulated microbial metabolites. Trilobatin (TLB) functions as a neuroprotective agent modulating gut microbiota. However, its capacity to alleviate depressive-like behavior and cognitive deficits through restoration of gut microbial ecology and metabolite profiles requires clarification.

OBJECTIVE: The present research was designed to examine the impact of TLB on depressive-like behavior and cognitive impairments, and the role of the gut microbiota and metabolites.

METHODS: Neuroprotective effects of TLB on MDD and AD were evaluated using an LPS mouse model exhibiting depressive-like behavior and memory impairment. The principal molecular target of TLB was identified through a combination of single-cell sequencing, surface plasmon resonance, and gene knockout approaches. Mechanistic insights into gut microbiota and metabolites were gained through 16S rRNA sequencing and fecal microbiota transplantation (FMT).

RESULTS: TLB attenuated LPS-induced depressive-like behaviors manifested as lowered sucrose preference, extended immobility, and improved cognitive deficits as reflected by Y-maze and novel object recognition. Mechanistically, TLB directly bound Nrf2, enhanced Nrf2-ARE activity, and suppressed neuroinflammation and oxidative stress. TLB restored gut microbiota homeostasis, elevated Akkermansia muciniphila (AKK) abundance and short-chain fatty acids, and strengthened intestinal tight junction proteins. FMT from TLB-treated mice replicated these benefits in wild-type but not Nrf2-knockout mice. AKK supplementation similarly ameliorated behavioral and cognitive deficits via Nrf2 activation.

CONCLUSION: Our findings reveal that TLB mitigates neuropsychiatric deficits by activating Nrf2, remodeling restructuring gut microbiota and fortifying intestinal barrier function. The Nrf2-mediated microbiota-gut-brain axis is suggested as a potential therapeutic target for MDD and AD, positioning TLB as a promising natural Nrf2 activator.},
}

@article {pmid41931996,
year = {2026},
author = {Liu, XY and Wang, K and Zhong, JJ and Lin, CL and Zhu, JR and Wang, PP and Guo, R and Shao, SS and Lim, HSD and Siow, KL and Shan Kek, R and Ng, YH and Chen, M and Han, RC and Yao, H and Zheng, GQ and Wen, L},
title = {Modified Kai-Xin-San ameliorates cognitive impairment in Alzheimer's disease model mice by regulating neuroinflammation and synaptic dysfunction.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158102},
doi = {10.1016/j.phymed.2026.158102},
pmid = {41931996},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by debilitating cognitive decline. Despite its escalating global prevalence, effective disease-modifying therapies remain limited. Modified Kai-Xin-San (MKXS), a derivative of a classic Chinese herbal formula, has shown promise in AD management; however, its precise pharmacological mechanisms require further elucidation.

PURPOSE: This study aimed to evaluate the therapeutic effects of MKXS and identify the molecular mechanisms underlying its impact on cognitive function in an AD mouse model.

METHODS: The chemical profile of MKXS was characterized using HPLC-Q-TOF-MS, with 24 major constituents quantified via UPLC-PDA. MKXS was administered intragastrically to 5 × FAD mice daily for two consecutive months. Cognitive performance was evaluated using Morris water maze, T-maze, and Y-maze tests. Neuropathological changes, including β-amyloid (Aβ) deposition and neuronal loss, were analyzed via immunostaining, Nissl staining, ELISA, and Western blotting. Synaptic plasticity was assessed through Golgi staining and electrophysiological recordings. Furthermore, network pharmacology and experimental validation were conducted to identify core therapeutic targets with the application of GEO database.

RESULTS: Chemical analysis identified 125 constituents in MKXS, with 24 validated against reference standards. In 5 × FAD mice, MKXS treatment significantly ameliorated cognitive impairment, reduced hippocampal Aβ plaque burden, and attenuated neuronal loss. Network pharmacology highlighted neuroinflammation and synaptic regulation as core therapeutic mechanisms. Subsequent validation demonstrated that MKXS suppressed glial overactivation and lowered pro-inflammatory cytokine levels, effectively restoring synaptic plasticity and dendritic spine integrity within the hippocampus. Notably, MKXS significantly upregulated the CaMKIIα/CREB signaling pathway in the hippocampus of 5 × FAD mice. Crucially, pharmacological inhibition of CaMKIIα with KN93 significantly abolished these beneficial effects on synaptic function and memory, confirming the essential role of this signaling axis in MKXS-mediated neuroprotection.

CONCLUSION: MKXS alleviated cognitive impairment in 5 × FAD mice by attenuating neuroinflammation and restoring synaptic integrity. These neuroprotective effects were mediated, at least in part, by the activation of the CaMKIIα/CREB signaling pathway. Collectively, these findings underscore the potential of MKXS as a promising multi-target therapeutic intervention for AD.},
}

@article {pmid41932135,
year = {2026},
author = {Lin, WJ and Li, CY and Shi, WP and Liu, TA and Wang, YJ and Li, YJ},
title = {Ferulic acid inhibits Tau-441 liquid-liquid phase separation to restore glycolytic metabolism.},
journal = {International journal of biological macromolecules},
volume = {358},
number = {},
pages = {151806},
doi = {10.1016/j.ijbiomac.2026.151806},
pmid = {41932135},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and effective clinical treatment currently remains lacking. Ferulic acid (FA) has shown clinical effects in the treatment of AD, but the underlying mechanism of action remains unclear. Here, we showed that FA significantly enhances glycolytic metabolism by inhibiting Tau-441 liquid-liquid phase separation (LLPS). Through molecular docking and solution experiments, we demonstrated that FA binds to Tau-441 via hydrogen bonds, significantly reducing its β-sheet content, thereby effectively preventing the formation of Tau-441 droplets and their transition into solid aggregates. Immunofluorescence staining further confirmed that FA inhibits Tau-441 LLPS formation and reduces the recruitment of hexokinase (HK) during droplet formation. Metabolomic and network analyses revealed that FA significantly alters cellular metabolic profiles, particularly enhancing glycolytic pathway activity. Consistently, FA markedly increased the activities of three key enzymes (HK, PFK, and PK) in the glycolytic pathway, thereby elevating cellular ATP levels and cell viability. These results demonstrate that FA significantly improves glycolytic metabolic efficiency by inhibiting Tau-441 LLPS, thus providing critical experimental and theoretical support for the potential application of FA in treating AD. Overall, this study offers new molecular targets and natural compound intervention strategies for AD treatment.},
}

@article {pmid41932344,
year = {2026},
author = {Geldenhuys, WJ and Mersch, J and Cicala, D and Sarker, R and Roknuzzaman, ASM and Maghareh, M and Carerra, EM and Lade, DM and Menze, MA and Konkle, ME and Huber, JD},
title = {Medicinal Chemistry Review of the NEET Protein Family.},
journal = {ChemMedChem},
volume = {21},
number = {7},
pages = {e202500969},
doi = {10.1002/cmdc.202500969},
pmid = {41932344},
issn = {1860-7187},
mesh = {Humans ; *Mitochondrial Proteins/metabolism/antagonists & inhibitors/chemistry ; Animals ; Ligands ; *Iron-Sulfur Proteins/metabolism/antagonists & inhibitors/chemistry ; },
abstract = {Members of the NEET family of proteins are of interest as drug targets in several age-related diseases, including cancer, diabetes, obesity, Alzheimer's and Parkinson's disease, stroke, and traumatic brain injury. These proteins share a CDGSH motif and redox-active [2Fe-2S] clusters. MitoNEET (CDGSH iron-sulfur domain-containing protein 1) is an outer mitochondrial membrane protein that was recently discovered as an off-target of the antidiabetic drug pioglitazone, and plays an essential role in mitochondrial bioenergetics, mitophagy, and iron metabolism. CDGSH iron-sulfur domain-containing protein 2 (nutrient-deprivation autophagy factor 1) is located on the endoplasmic reticulum and is found to be antiaging and associated with Wolfram Syndrome 2, while CDGSH iron-sulfur domain-containing protein 3 (mitochondrial inner NEET protein) is present in the mitochondrial matrix. In this review, we will evaluate the state of the field in the development of NEET protein interacting ligands, which can serve as pharmacological tools to study the biology/biochemistry of NEET family proteins in disease. The NEET family represents a novel class of drug targets, enabling the development of novel treatment modalities to modulate disease progression in various human disorders.},
}

Humans
*Mitochondrial Proteins/metabolism/antagonists & inhibitors/chemistry
Animals
Ligands
*Iron-Sulfur Proteins/metabolism/antagonists & inhibitors/chemistry

@article {pmid41867219,
year = {2026},
author = {Jannati, A and Toro-Serey, C and Ciesla, M and Chen, E and Showalter, J and Bates, D and Pascual-Leone, A and Tobyne, S},
title = {Streamlining Eligibility Assessment for Alzheimer's Disease-Modifying Therapies: Prediction of MMSE Scores Using the Digital Clock and Recall.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {41867219},
abstract = {INTRODUCTION: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks perpetuating health disparities due to the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR[™]) - a rapid, FDA-listed digital cognitive assessment - to crosswalk to MMSE scores using machine learning, thereby offering a faster, scalable, and equitable mechanism for patient triage.

METHODS: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 study (NCT04733989, N=945). Participants were clinically classified as cognitively unimpaired, mild cognitive Impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was tested for generalizability using an independent external validation cohort from the Apheleia study (NCT05364307, N=238).

RESULTS: The machine learning model predicted MMSE scores with a root mean squared error (RMSE) of 2.31 in the training cohort. This error margin falls within the established test-retest reliability range of the manual MMSE itself (2-4 points), suggesting the prediction is statistically non-inferior to human administration. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE = 2.62). Crucially, the model exhibited demographic fairness, maintaining consistent accuracy across Race (White RMSE = 2.34; Non-White RMSE = 2.14) and Ethnicity (Hispanic RMSE = 2.26; Non-Hispanic RMSE = 2.31).

DISCUSSION: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.},
}

@article {pmid41922883,
year = {2026},
author = {Shah, D and Akarte, K and Patel, S and Patel, A and Kushwaha, N and Panjwani, D and Patel, V and Ahlawat, P and Shah, A},
title = {Recent Progress on Selenium Nanoparticles: Synthesis and Neuroprotective Effects for the Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41922883},
issn = {1559-1182},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Neuroprotective Agents/chemical synthesis/therapeutic use/pharmacology ; Animals ; *Nanoparticles/chemistry/therapeutic use ; *Selenium/therapeutic use/chemistry ; },
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia, affecting over 50 million individuals worldwide, with projections suggesting a tripling of cases by 2050. Current Food and Drug Administration (FDA)-approved treatments, including cholinesterase inhibitors, N-Methyl-D-aspartic acid (NMDA) receptor antagonists, and monoclonal antibodies, provide only modest symptomatic relief or partial disease modification. Their limitations include poor blood-brain barrier penetration, systemic side effects, and reduced efficacy in advanced stages. This has caused the exploration of novel nanotechnology-based interventions. This review synthesizes recent evidence from preclinical and translational studies on SeNPs for AD therapy. Also covering their synthesis methods (physical, chemical, and biological), surface engineering approaches, drug loading strategies, and mechanisms of action were systematically examined. SeNPs exhibit dual functionality as therapeutic agents and drug carriers. Functionalized SeNPs have shown the ability to cross the BBB, but this efficiency depends on particle size (typically < 100 nm) and surface ligands such as transferrin, rabies virus glycoprotein 29-peptide (RVG29), or transferrin-guiding peptide (TGN). Studies using ligand-modified SeNPs demonstrate improved BBB transport and enhanced modulation of oxidative stress, amyloid-β (Aβ) aggregation, and neuroinflammation. SeNPs exhibit neuroprotective activity in several preclinical models, primarily attributed to antioxidant and anti-inflammatory mechanisms. Although encouraging preclinical data support their promise, systematic toxicological assessment and optimization of stability are required. With advances in green synthesis, surface engineering, and theranostic applications, SeNPs may represent a new Framework in precision nanomedicine for Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy
Humans
*Neuroprotective Agents/chemical synthesis/therapeutic use/pharmacology
Animals
*Nanoparticles/chemistry/therapeutic use
*Selenium/therapeutic use/chemistry

@article {pmid41922909,
year = {2026},
author = {Dai, Q and Lin, Q and Chen, J and Deng, Z and Jin, W and Ye, P and Zuo, Y and Yang, Y and Xiao, S and Tang, Y},
title = {Prevalence and burden of neurological diseases in the Chinese mainland: An analysis from the Global Burden of Disease Study 2021.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {41922909},
issn = {2542-5641},
abstract = {BACKGROUND: Neurological diseases represent a growing challenge to the Chinese public health system. However, a comprehensive analysis of neurological diseases in China is lacking. This study aimed to analyze disease burden and risk factors of neurological diseases in the Chinese mainland to identify priorities for disease control and prevention.

METHODS: Disease burden and risk factors in the Chinese mainland were analyzed for 12 neurological disorders using data from the Global Burden of Diseases 2021 study and the Chinese Center for Disease Control and Prevention. Prevalence, deaths, years of life lost, years lived with disability (YLDs), and disability-adjusted life years (DALYs) were used as metrics.

RESULTS: Intracerebral hemorrhage (ICH) (1930.3 [95% uncertainty interval (UI): 1605.3-2296.7] per 100,000), ischemic stroke (1646.8 [95% UI: 1400.0-1893.1] per 100,000), Alzheimer's disease and other dementias (dementia) (708 [95% UI: 347.7-1561.7] per 100,000) made the greatest contributions to DALY rates in the Chinese mainland in 2021. The fastest growing contributors to DALY rates were dementia (208.2% [95% UI: 166.4-255.7%]), Parkinson's disease (160.7% [95% UI: 121.8-208.3%]), and ischemic stroke (95.2% [95% UI: 56.9-140.6%]). Migraine was the leading contributor to DALY rates among populations aged 10-39 years, ICH for those aged 40-74 years, ischemic stroke for those aged 75-89 years, and dementia for those aged >90 years. Ischemic stroke accounted for the highest age-standardized DALY rates in North and Northeast China, whereas ICH ranked first in other regions. High systolic blood pressure had the highest attributable DALYs for all diseases combined. Metabolic risk factors, alcohol use, secondhand smoke, and low physical activity contributed to higher YLDs in females, whereas alcohol use, smoking, and a high-sodium diet contributed to higher YLDs in males.

CONCLUSIONS: Neurological diseases present a growing public health challenge, characterized by significant disparities in their prevalence and presentation across age, sex, and geographic regions. Addressing these disparities requires coordinated strategies encompassing prevention, treatment, rehabilitation, and supportive care at the national level.},
}

@article {pmid41923420,
year = {2026},
author = {Luzzi, S and Snowden, JS},
title = {Low Sensitivity of Neuropsychological Scales Hinder Detection of Potential Benefit of Treatments in Alzheimer's Disease: A Position Paper.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70590},
pmid = {41923420},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/diagnosis/drug therapy/psychology ; *Neuropsychological Tests/standards ; Cognitive Dysfunction/diagnosis ; Sensitivity and Specificity ; },
abstract = {BACKGROUND: Despite the advent of Disease Modifying Therapies (DMTs) for Alzheimer's Disease (AD), the approval and commercialization of anti-amyloid monoclonal antibodies has been slow and contentious, particularly in Europe. The primary source of debate is the discrepancy between robust biological effects-namely, effective β-amyloid clearance-and modest clinical improvements, which, although statistically significant, often fail to reach the minimal clinically important difference (MCID) compared to placebo.

METHODS: This paper highlights a confounding factor in the interpretation of the results of clinical trials: limited sensitivity of neuropsychological outcome measures. These tools, developed in the 1980s and only marginally updated, are not suited to detect subtle but meaningful cognitive changes in early disease stages.

RESULTS: The ADAS-Cog, the most commonly used cognitive endpoint, suffers from a substantial ceiling effect, impairing its ability to capture cognitive decline over short durations in prodromal populations. Likewise, functional scales such as the CDR-SB are inherently insensitive in mild cognitive impairment (MCI), as functional independence is, by definition, preserved. Moreover, the use of composite multidomain scales with high baseline scores may mask domain-specific improvements, further limiting a drug's capacity to reach MCID thresholds.

CONCLUSION: Methodological limitations risk undervaluing the therapeutic impact of treatment, particularly in trials targeting early or preclinical phases where changes are subtle and domain-specific. Urgent reconsideration of outcome measures is necessary to ensure accurate assessment of clinical efficacy and to avoid prematurely discarding potentially beneficial therapies.},
}

Humans
*Alzheimer Disease/diagnosis/drug therapy/psychology
*Neuropsychological Tests/standards
Cognitive Dysfunction/diagnosis
Sensitivity and Specificity

@article {pmid41924980,
year = {2026},
author = {Chaulagain, B and Gothwal, A and Mahanta, AK and Jarajapu, YPR and Singh, J},
title = {Cannabidiol and pBDNF Cotreatment Attenuates Pathological Symptoms and Improves Cognition in 3 month-Old 5XFAD Mice.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c01009},
pmid = {41924980},
issn = {1948-7193},
abstract = {The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a synaptic modulation and cognitive maintenance agent, is declined and, thus, aggravates pathology and cognition in AD. BDNF expressed from the liposome nanoparticles supplements the reduced BDNF and aids in ameliorating AD pathology. We found four weekly doses of our formulation reduced the amyloid burden by 3.04-fold (p-value < 0.0001), declined pro-inflammatory cytokines TNF-α by 2.51-fold (p-value < 0.0001), IL-1β by 2.34-fold (p-value < 0.0001) and microglial activation by 2.15-fold (p-value < 0.0001) than saline controls. In addition, it increased the synaptic markers level and promoted adult hippocampal neurogenesis, eventually improving cognitive functions. These findings suggest the use of CBD and pBDNF has a potential therapeutic combination for AD management if intervened early.},
}

@article {pmid41925793,
year = {2026},
author = {Ramanan, S and Johnson, GVW},
title = {A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimer's and Parkinson's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {2},
pages = {},
pmid = {41925793},
issn = {1559-1166},
support = {R01AG073121/GF/NIH HHS/United States ; },
mesh = {Humans ; *Parkinson Disease/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics ; *Transcription Factors/metabolism/genetics ; Computational Biology ; *DNA-Binding Proteins/metabolism/genetics ; Animals ; *Adaptor Proteins, Signal Transducing/metabolism/genetics ; Signal Transduction ; *Apoptosis Regulatory Proteins/metabolism/genetics ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.},
}

Humans
*Parkinson Disease/metabolism/genetics
*Alzheimer Disease/metabolism/genetics
*Transcription Factors/metabolism/genetics
Computational Biology
*DNA-Binding Proteins/metabolism/genetics
Animals
*Adaptor Proteins, Signal Transducing/metabolism/genetics
Signal Transduction
*Apoptosis Regulatory Proteins/metabolism/genetics

@article {pmid41925947,
year = {2026},
author = {Patwekar, F and Patwekar, M and Wei, LS and Sharma, R and Varghese, R and Mohammed, A},
title = {Advancing diagnostic biomarkers in Alzheimer's disease: interdisciplinary innovations and technological frontiers.},
journal = {Human cell},
volume = {39},
number = {4},
pages = {},
pmid = {41925947},
issn = {1749-0774},
mesh = {*Alzheimer Disease/diagnosis/metabolism/genetics ; Humans ; *Biomarkers/metabolism ; Biosensing Techniques ; Machine Learning ; tau Proteins ; Nanotechnology ; Precision Medicine ; *Inventions/trends ; Positron-Emission Tomography ; *Interdisciplinary Research ; Magnetic Resonance Imaging ; Amyloid beta-Peptides ; Early Diagnosis ; Artificial Intelligence ; },
abstract = {Developing diagnostic biomarkers for Alzheimer's disease (AD) is at the cutting edge of interdisciplinary research and technical advancement. This comprehensive analysis investigates potential options for improving diagnostic accuracy and early detection of AD. Identifying biomarkers other than Aβ and tau proteins, such as synaptic dysfunction markers and metabolic indicators, is a novel technique. Integrating multi-omics data provides a comprehensive picture of AD pathophysiology, assisting in the discovery of biomarkers and treatment targets. Advances in technology, notably nanotechnology and biosensors, show promise for highly sensitive and specific platforms capable of identifying AD-related biomarkers in physiological fluids. AI and machine learning algorithms are critical in analyzing large datasets, improving pattern identification, and increasing diagnostic accuracy. Predictive models based on various biomarkers and clinical data open the way for personalized medicine methods in the treatment of AD. More advancements in PET and MRI tracers are required for targeted and sensitive imaging of specific AD-related clinical alterations. Wearing gadgets and seeing digital health signs have helped us to find diseases early and track them over time. They even allow monitoring from afar and all the time. This comprehensive review brings together new developments and teamwork across different fields. In this way, it guides to enhance how to identify AD. By mixing these new methods, we aim to change the diagnosis of AD early and accurately. This allows us to focus on treatments and push forward new cures for AD.},
}

*Alzheimer Disease/diagnosis/metabolism/genetics
Humans
*Biomarkers/metabolism
Biosensing Techniques
Machine Learning
tau Proteins
Nanotechnology
Precision Medicine
*Inventions/trends
Positron-Emission Tomography
*Interdisciplinary Research
Magnetic Resonance Imaging
Amyloid beta-Peptides
Early Diagnosis
Artificial Intelligence

@article {pmid41925951,
year = {2026},
author = {Feng, JQ and Yang, LL and Luo, YX and Yao, XQ},
title = {Alzheimer's disease: from molecular pathways to therapies.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {41925951},
issn = {2662-8651},
support = {No.82371427//National Natural Science Foundation of China/ ; No.82401656//National Natural Science Foundation of China/ ; CSTB2023NSCQ-MSX0323//Natural Science Foundation of Chongqing Municipality/ ; 2025MSXM044//Joint project of Chongqing Health Commission and Science and Technology Bureau/ ; CYB240199//Postgraduate Research and Project of Chongqing Province/ ; },
mesh = {*Alzheimer Disease/therapy/metabolism/pathology/etiology ; Humans ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Animals ; Immunotherapy/methods ; Gastrointestinal Microbiome ; Signal Transduction ; },
abstract = {Alzheimer disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide. With accelerating population aging, its incidence continues to rise, imposing a substantial burden on public health systems and society. Despite extensive advances in research, currently available therapies remain largely symptomatic and have limited capacity to halt or reverse disease progression. Recent progress in understanding the molecular and cellular mechanisms underlying AD has driven the development of targeted therapeutic strategies, particularly immunotherapies directed against amyloid-β (Aβ) and tau pathology. However, the pathogenesis of AD is highly complex and multifactorial, underscoring the need for a more integrated understanding of the interactions among diverse pathological processes and the identification of additional therapeutic targets. Here, we provide a systematic synthesis of the core pathological mechanisms of AD and their interconnected molecular pathways, together with a comprehensive overview of current targeted therapeutic strategies. We highlight recent advances in Aβ- and tau-directed immunotherapies and further examine emerging interventions targeting neuroinflammation, metabolic dysregulation, the gut microbiota, lifestyle-related factors, and neurogenesis, evaluating their potential based on evidence from both clinical and preclinical studies. By integrating mechanistic insights with therapeutic developments, this review outlines key opportunities and challenges in the evolving landscape of AD treatment. These perspectives may inform the development of next-generation disease-modifying therapies and contribute to a more comprehensive framework for understanding the pathogenesis and treatment of AD.},
}

*Alzheimer Disease/therapy/metabolism/pathology/etiology
Humans
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Animals
Immunotherapy/methods
Gastrointestinal Microbiome
Signal Transduction

@article {pmid41926104,
year = {2026},
author = {Devanand, DP and Wei, R and Qian, M},
title = {Treatment of Early Symptomatic Alzheimer Disease With Valacyclovir-Reply.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.1105},
pmid = {41926104},
issn = {1538-3598},
}

@article {pmid41926105,
year = {2026},
author = {Kosaka, M and Kami, M},
title = {Treatment of Early Symptomatic Alzheimer Disease With Valacyclovir.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2026.1102},
pmid = {41926105},
issn = {1538-3598},
}

@article {pmid41903899,
year = {2026},
author = {Green, MC and Braun, DJ and Leibold, CT and Van Eldik, LJ and Bailey, CS},
title = {Specific inhibition of p38α MAPK dampens neuroinflammation during acute alcohol withdrawal in mouse BV2 microglial cell line and rat organotypic hippocampal slice cultures.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {133},
number = {},
pages = {32-37},
doi = {10.1016/j.alcohol.2026.03.007},
pmid = {41903899},
issn = {1873-6823},
abstract = {Neuroinflammation is implicated in anxiety and negative affect in alcohol withdrawal, potentially contributing to relapse. The mitogen-activated protein kinase p38α (p38) is a critical driver of neuroinflammation in such excitatory neural contexts, and its inhibition reduces neuroinflammatory cytokine production in the context of various insults generally corresponding with improved cellular and synaptic health. Although heretofore unexamined, we hypothesized that inhibition of p38 by small-molecule MW150 would reduce neuroinflammation during the acute alcohol withdrawal period. Immortalized mouse BV2 and post-natal day 8 rat organotypic hippocampal slice cultures received 50mM ethanol in media for 24 h followed by 24 h withdrawal, or for 48 h continuously, with administration of 5 μM MW150 or saline for the final 24 h of treatment. Control tissue never received ethanol. Levels of cytokines in the culture media were analyzed after 48 h by MesoScale ELISA assays. Elevated CXCL1 and TNFα levels were ameliorated by MW150 during ethanol withdrawal in culture media from BV2 and female OHSC, respectively. Further, MW150 reduced TNFα, but increased IL6, across all conditions in the BV2 microglia. Preliminary evidence suggests that p38 inhibition during early ethanol withdrawal in vitro reduces select inflammatory cytokines. Given that MW150 is presently in clinical trials for neuroinflammation in Alzheimer's disease, its preclinical validation for use in alcohol withdrawal in vivo is crucial to determine its feasibility to modulate neuroinflammation and problem drinking in humans.},
}

@article {pmid41916153,
year = {2026},
author = {Wang, C and Xu, X and Zhu, H and Wu, D and Liang, J and Wang, X and Song, R and Shen, L and Hu, Y and Wang, D and Zhu, H and Cheng, X and Qi, Y},
title = {Acori tatarinowii Rhizoma-Curcumae Radix herbal pair ameliorates cognitive impairment and suppresses neuro-inflammation via Ca[2+]/CaMKKβ/AMPK/mTOR pathway in Alzheimer's disease.},
journal = {Journal of ethnopharmacology},
volume = {365},
number = {},
pages = {121606},
doi = {10.1016/j.jep.2026.121606},
pmid = {41916153},
issn = {1872-7573},
abstract = {Effective activation of neuronal autophagy and clearance of amyloid-beta (Aβ) represents a promising therapeutic strategy in the treatment of Alzheimer's disease (AD). The Acori Tatarinowii Rhizoma-Curcumae Radix Herbal pair (ACHP), derived from the traditional Changpu Yujin Decoction, has a long history in Traditional Chinese Medicine for addressing conditions related to cognitive function. However, the precise mechanisms underlying its role in autophagic dysfunction-related dementia remain unclear.

AIM OF THE STUDY: This study aims to investigate the neuroprotective effects of ACHP and the underlying mechanisms in AD.

MATERIALS AND METHODS: Analysis of prototype constituents in drug-containing serum was performed using UHPLC-Triple-TOF/MS. The neuroprotective effects of ACHP were evaluated in APP/PS1 mice using behavioral tests, including the Y-maze and Morris water maze. Transcriptomic analysis was conducted to identify potential neuroprotective pathways activated by ACHP. Neuronal damage and structural recovery were assessed through HE and Nissl staining. In addition, the anti-inflammatory and autophagy-regulating effects of ACHP were further investigated in N2a/APP cells. The molecular mechanisms were further elucidated using Western blot, immunofluorescence, ELISA, and qRT-PCR in both in vivo and in vitro models.

RESULTS: Twenty-five compounds in ACHP-treated mouse serum were identified. ACHP improved spatial learning and memory performance, increased intracellular Ca[2+] levels and downregulated the expressions of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, while significantly promoting autophagy. ACHP increased CaMKKβ protein expression and activated the AMPK signaling pathway (elevated p-AMPK/AMPK ratio), as well as those of autophagy-related proteins, while improving neuronal morphology.

CONCLUSION: These findings indicate that ACHP alleviates neuro-inflammatory damage and cognitive impairment potentially through modulation of the Ca[2+]/CaMKKβ-AMPK-mTOR signaling pathway involved in autophagy.},
}

@article {pmid41916976,
year = {2026},
author = {Parent, O and Alasmar, Z and Osborne, S and Bussy, A and Costantino, M and Fouquet, JP and Quesada, D and Pastor-Bernier, A and Fajardo-Valdez, A and Pichet-Binette, A and McQuarrie, A and Maranzano, J and Devenyi, GA and Steele, CJ and Villeneuve, S and , and , and Dadar, M and Chakravarty, MM},
title = {Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-70832-2},
pmid = {41916976},
issn = {2041-1723},
abstract = {White matter hyperintensities (WMHs) are neuroimaging markers widely interpreted as caused by cerebral small vessel disease, yet emerging evidence suggests that a subset may have a neurodegenerative etiology. Current imaging methods have lacked the specificity to disentangle biological processes underlying WMHs in vivo. Here, we used voxel-level normative modeling and seven microstructural MRI markers with complementary biophysical sensitivities to generate single-subject high-resolution WMH pathophysiology maps in a large cohort (n = 32,526). We calculated data-driven spatial patterns of similar WMHs, revealing distinct periventricular, posterior, and anterior clusters. We identified a reproducible WMH signature linked to dementia and Alzheimer's disease, characterized by a posterior predominance and a pathophysiological pattern indicative of selective fiber degeneration. Posterior WMHs connected cortical regions vulnerable to tau pathology. Our framework helps parsing vascular and neurodegenerative contributions of WMHs in vivo, which could alter the course of treatment strategies and provide nuanced interpretations of research findings.},
}

@article {pmid41918193,
year = {2026},
author = {Behrouzfar, H and Mortazavi, P and Hassani, S and Aghebat Bekheir, S},
title = {Exploring the Effects of Empagliflozin Administration and Physical Training on Cognitive Functions in an Amyloid Beta-Induced Alzheimer's Rat Model.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673434008260121111535},
pmid = {41918193},
issn = {1875-533X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a widely prevalent and neurodegenerative disorder that leads to dementia and mortality worldwide. Previous investigations have reported the beneficial effects of physical exercise on brain function, linked to anti-inflammatory effects in the brain vasculature and elevated BDNF production. Empagliflozin, a conventional antidiabetic agent, has shown potential neuroprotective properties in the central nervous system, evidenced by its ability to elevate BDNF and mitigate oxidative stress and inflammation.

MATERIALS AND METHODS: In the present investigation, AD was induced in control, exercise, empagliflozin (10 mg/kg BW, PO), and combined intervention groups using intrahippocampal injections of an amyloid-beta (Aβ) prepared solution via stereotaxic surgery. The therapeutic effects of each treatment, exercise alone, empagliflozin alone, and exercise plus empagliflozin, were studied. After 28 days, spatial memory tests were used to assess memory and learning. Furthermore, histopathological (H&E and Congo red) and immunohistochemical (GFAP) analyses were performed, and the ADP/ATP ratio in isolated brain mitochondria was measured by HPLC.

RESULTS: Our results showed that the combined program of physical training and empagliflozin treatment in the Aβ-induced AD model drastically improved cognitive functions and neurological parameters, including target-finding time, traveled distance, time spent in the target quadrant, and ADP/ATP ratios in brain mitochondria. Additionally, it diminished necrotic cell death and reduced Aβ plaques but did not notably affect astrocyte activity.

DISCUSSION: Exercise and empagliflozin, by affecting mitochondrial energy balance and reducing amyloid deposition, play key roles in mitigating AD pathophysiology.

CONCLUSION: The combined effects of the treatments used in this experimental method yielded significant improvements in cognitive functions. These findings provide a basis for further clinical studies for the exploration of the synergistic impact of the aforementioned therapeutic methods.},
}

@article {pmid41918201,
year = {2026},
author = {Sharma, S and Sharma, D and Sharma, A},
title = {Targeting Vascular Dementia: Pharmacological Mechanisms and Therapeutic Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273440657260226125023},
pmid = {41918201},
issn = {1996-3181},
abstract = {INTRODUCTION: Vascular dementia is a leading cause of cognitive deterioration worldwide, caused by a complex interplay of pathological mechanisms such as disrupted cerebral blood flow, oxidative stress, neuroinflammation, and endothelial dysfunction. A clear knowledge of these mechanisms is crucial for developing efficient treatment strategies. Various drug classes, including statins, cholinesterase inhibitors, anti-diabetic drugs, leukotriene antagonists, and nootropics, offer promising approaches by addressing different facets of this multifaceted condition. This review's objective is to offer a comprehensive analysis of the functional mechanisms of diverse pharmacological agents in curing vascular dementia. It further aims to identify their therapeutic potential, limitations, and areas requiring future research.

METHODOLOGY: A review of the literature was conducted to examine evidence from preclinical and clinical research. Pharmacological chemicals were evaluated for their effects on key pathological pathways, including oxidative stress, inflammation, endothelial dysfunction, and impaired neurotransmission.

RESULT AND DISCUSSION: Each class of drugs reviewed demonstrates distinct benefits in addressing specific aspects of vascular dementia. Statins primarily mitigate vascular risk factors and neuroinflammation, while cholinesterase inhibitors enhance neurotransmitter availability to support cognitive function. Anti-diabetic drugs exhibit neuroprotective properties through metabolic regulation and antiinflammatory effects, and leukotriene antagonists show potential in reducing oxidative damage and inflammation. Nootropics, on the other hand, focus on enhancing synaptic plasticity and memory. Despite these promising mechanisms, limitations such as inconsistent clinical outcomes, potential adverse effects, and the absence of individualized treatment protocols remain significant challenges.

CONCLUSION: This review emphasizes the need for developing integrated therapeutic strategies that target the diverse pathological mechanisms underlying vascular dementia. While current pharmacological approaches show considerable potential, there is a desperate need for long-term clinical validation and the development of personalized medicine frameworks. Advances in diagnostic tools, biomarkers, and imaging technologies will be crucial for early diagnosis and effective disease monitoring, paving the way for improved patient results and a more profound understanding of vascular dementia's complexity.},
}

@article {pmid41918343,
year = {2026},
author = {Lopes, SP and Emídio, JJ and Duarte, ABS and Orhan, IE and Deniz, FSS and Salmas, RE and de Sousa, DP},
title = {Synthesis of p-Coumarates With Potential Anti-Alzheimer's Action: Enzyme Inhibition and In Silico Studies.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {4},
pages = {e03857},
doi = {10.1002/cbdv.202503857},
pmid = {41918343},
issn = {1612-1880},
support = {306661/2016-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
mesh = {*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology ; *Butyrylcholinesterase/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism ; Humans ; *Coumaric Acids/chemistry/chemical synthesis/pharmacology ; Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Structure ; Dose-Response Relationship, Drug ; Propionates/chemistry/chemical synthesis/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a fatal neurodegenerative disorder that affects cognition, memory, and behavior. Such a disease is considered the most common cause of dementia and affects a large portion of the elderly population worldwide. Currently, cholinesterase inhibitors are used to reduce the symptoms and rate of progression of this disease. Thus, the present study evaluated the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of a set of 22 p-coumarate derivatives using the spectrophotometric method. The inhibitory activity of the compounds against AChE and BChE was measured using the adapted Ellman spectrophotometric method; the reported inhibition percentages were determined at a final concentration of 100 µM. The structures of the synthesized compounds were characterized by FTIR, [1]H-NMR, [13]C-NMR, and HRMS spectroscopy. Among the compounds tested, three showed moderate inhibitory activity against AChE and good activity against BChE: (E)-4-chlorobenzyl 3-(4-hydroxyphenyl)acrylate (14) (56.36%; 75.17%), (E)-4-bromobenzyl 3-(4-hydroxyphenyl)acrylate (15) (61.11%; 76.09%), and (E)-naphthalene 3-(4-hydroxyphenyl)acrylate (18) (59.18%; 65.39%), respectively. Compound 15 had an IC50 of 22.22 ±1.50 mM against BChE, which is notably better than galantamine's BChE inhibition. The in silico analysis suggested that compounds 14, 15, and 18 interact with AChE and BChE. Thus, p-coumaric acid derivatives represent promising prototypes for the search for new drug candidates for the treatment of AD.},
}

*Cholinesterase Inhibitors/chemical synthesis/chemistry/pharmacology
*Butyrylcholinesterase/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Acetylcholinesterase/metabolism
Humans
*Coumaric Acids/chemistry/chemical synthesis/pharmacology
Structure-Activity Relationship
Molecular Docking Simulation
Molecular Structure
Dose-Response Relationship, Drug
Propionates/chemistry/chemical synthesis/pharmacology

@article {pmid41919006,
year = {2026},
author = {Buchanan, TJ and Ewen, C and Rebollo Mesa, I and Germani, M and Watanabe, S and Jose, J and Famodimu, O and Colson, AO and De Bruyn, S},
title = {Two phase 1 randomised studies investigating the safety and pharmacokinetics of bepranemab in healthy participants of different ethnicities.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001395},
pmid = {41919006},
issn = {2632-6140},
abstract = {BACKGROUND: Bepranemab is a recombinant, humanised, full-length IgG4 monoclonal antibody targeting a mid-region tau epitope. Two phase 1 studies assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of bepranemab.

METHODS: UP0047 (NCT03464227) and UP0065 (NCT03605082) were phase 1, double-blind, placebo-controlled, single-dose, dose-escalation studies of intravenous bepranemab in healthy participants (Caucasian and Japanese descent, respectively). Primary endpoint: safety and tolerability of single ascending doses of bepranemab. PK were assessed in serum and cerebrospinal fluid (CSF); PD (levels of free tau) in CSF. A physiologically based PK/PD (PBPK/PD) model was developed to predict dose response.

RESULTS: UP0047: Caucasian participants (N=52) were randomised to bepranemab 0.3 mg/kg, n=2; 1 mg/kg, n=6; 3 mg/kg, n=6; 10 mg/kg, n=6; 30 mg/kg, n=6; 60 mg/kg, n=6; 120 mg/kg, n=6; placebo, n=14). UP0065: participants of Japanese descent (N=24) were randomised to bepranemab 30 mg/kg, n=6; 60 mg/kg, n=6; 120 mg/kg, n=6; placebo, n=6). No serious treatment-emergent adverse events (TEAEs) or discontinuations due to TEAEs were observed. One participant (bepranemab 60 mg/kg) experienced treatment-related TEAEs of headache (moderate intensity), nausea and vomiting (mild intensity). There was no effect of ethnicity on PK parameters. A dose-response effect of bepranemab on free tau levels was observed. Data applied to a PBPK/PD model supported a dose of 90 mg/kg of bepranemab every 4 weeks to achieve a reduction in mean change from baseline in free tau levels of up to 90%.

CONCLUSIONS: Safety, PK and PD data support continued investigation of bepranemab for the treatment of tauopathies.},
}

@article {pmid41919455,
year = {2026},
author = {Fujioka, S and Nagaishi, Y and Imamura, T and Minagawa, H and Uwatoko, K and Yukitake, M and Kira, JI and Tsuboi, Y},
title = {Amyloid PET-guided anti-amyloid therapy in corticobasal syndrome associated with clinical improvement.},
journal = {Neurologia i neurochirurgia polska},
volume = {},
number = {},
pages = {},
doi = {10.5603/pjnns.110307},
pmid = {41919455},
issn = {0028-3843},
abstract = {AIM OF THE STUDY: Corticobasal syndrome (CBS), a heterogeneous clinical phenotype, can be associated with various underlying pathologies. Although neuropathological studies show that CBS cases can be attributed to Alzheimer's disease (AD), in vivo confirmation and subsequent disease-modifying therapy remain rarely reported. In our patients presenting with clinical features consistent with CBS, amyloid positron emission tomography (PET) facilitated the diagnosis of underlying AD pathology and enabled the initiation of anti-amyloid therapy.

MATERIAL AND METHODS: We retrospectively reviewed patients with probable corticobasal degeneration from two tertiary centers who underwent amyloid PET confirming AD, systematically collecting clinical, imaging, and treatment data.

RESULTS: Two patients were identified who fulfilled the inclusion criteria. In both patients, episodic memory was impaired, which was inconsistent with a typical corticobasal syndrome phenotype. Amyloid PET demonstrated widespread cortical and subcortical amyloid deposition, confirming underlying AD pathology. Based on these findings, anti-amyloid therapy was initiated, and clinical improvement was observed in both patients, although causality cannot be inferred from this uncontrolled retrospective observation.

CONCLUSIONS: Corticobasal syndrome may be an atypical clinical presentation of AD pathology. Importantly, molecular imaging allowed an in vivo diagnosis of AD and facilitated the timely initiation of anti-amyloid therapy.

CLINICAL IMPLICATIONS: This novel report documents the clinical implementation of amyloid PET guided anti-amyloid therapy in patients presenting with CBS.},
}

@article {pmid41920507,
year = {2026},
author = {Lan, H and Zhang, J and Zhao, Z and Liu, X and Rao, C},
title = {Focal-DenseNet: A Risk Assessment Framework for Alzheimer's Disease in Heterogeneous MRI Data.},
journal = {Interdisciplinary sciences, computational life sciences},
volume = {},
number = {},
pages = {},
pmid = {41920507},
issn = {1867-1462},
support = {S202410497177//National Undergraduate Innovation and Entrepreneurship Training Program/ ; 25YJAZH138//Planning Fund Project of the Ministry of Education's Humanities and Social Sciences Research/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease of the nervous system, which has become an important public health issue attracting global attention. However, its exact causes and pathogenesis have not been fully elucidated, and the existing treatment methods and intervention measures have limited efficacy. Therefore, how to establish a scientific and efficient risk assessment mechanism has become the key to the prevention and treatment of AD. Aiming at this problem, this paper optimizes the convolutional neural network structure of DenseNet and proposes a Focal-DenseNet model that integrates the focal loss function for the risk assessment and diagnostic prediction of AD. First of all, preprocess the collected data to ensure the data quality for subsequent analysis. Secondly, establish the Focal-DenseNet model. Finally, use the model for training and testing. The test results show that the test set accuracy of the model reaches 98.98%, indicating that the model performs well. In addition, this paper also compares the proposed model with the DenseNet model without using the focal loss function and other common deep learning models (such as VGG16, ResNet, etc.). The results show that the model in this paper exhibits superiority in multiple performance indicators. In particular, it has achieved high scores in key indicators such as accuracy, AUC (the area under the receiver operating characteristic curve), precision, and recall. This study provides an efficient technical support for the early risk assessment of AD, and holds significant clinical application value and academic reference significance for improving the prevention and treatment level of AD and reducing the global public health burden.},
}

@article {pmid41920573,
year = {2026},
author = {Pathak, US and Mehralizade, A and Goldberg, TE and Zoghbi, AW},
title = {Dementia in Severe Schizophrenia.},
journal = {JAMA psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamapsychiatry.2026.0171},
pmid = {41920573},
issn = {2168-6238},
abstract = {IMPORTANCE: Dementia develops in individuals with schizophrenia 4- to 20-fold more frequently than in the general population, but its etiology remains unexplained.

OBJECTIVE: To characterize the cognitive, clinical, and genetic features of dementia in individuals with severe, extremely treatment-resistant schizophrenia (SETRS).

This retrospective cohort study among individuals with SETRS was conducted at New York state hospitals from December 2017 through July 2019. All participants met DSM-5 schizophrenia criteria and were continuously hospitalized for 5 years or more. Exclusion criteria included forensic hospitalization, known medical causes of psychosis, or recent substance abuse. Cognitive, clinical, and genetic data were compared to data from individuals from the National Alzheimer Coordinating Center dataset, including those with Alzheimer disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), or vascular dementia (VD), along with healthy controls. Data were analyzed from January 2025 through December 2025.

MAIN OUTCOMES AND MEASURES: Multiple regression was used to analyze the effects of demographic, clinical, and genetic factors on the Montreal Cognitive Assessment (MoCA).

RESULTS: In this study's cohort of 155 individuals with SETRS (mean [SD] age, 59.3 [10.3] years; 56 female participants [36.1%]), 153 of 155 (98.7%) scored below the cutoff of 26 for mild cognitive impairment, and 73 of 155 (47.1%) scored below the cutoff of 10 for severe dementia (mean [SD] MoCA score, 9.8 [6.4]). At the item level, the MoCA profile of SETRS differed from those of AD and FTD but paralleled that of community-dwelling individuals with schizophrenia (Pearson r = 0.86; P < .001). No participants carried pathogenic variants in mendelian dementia genes; APOE4 allele frequency was significantly lower in SETRS (14.4%) than in AD (33.6%; odds ratio [OR], 0.33; 95% CI, 0.20-0.53; P < .001) or LBD (24.7%; OR, 0.51; 95% CI, 0.29-0.89; P = .01). Cognitive impairment was not attributable to premorbid intellectual disability, poor effort, medications, cardiometabolic risk factors, or institutionalization.

CONCLUSIONS AND RELEVANCE: In this cohort study of 155 individuals with SETRS, none of the commonly proposed explanations for schizophrenia dementia (eg, comorbid Alzheimer disease or cardiovascular risk factors) proved viable. The pattern of cognitive impairments differed from those of Alzheimer disease, frontotemporal dementia, and Lewy body dementia, but recapitulated and intensified that of community-dwelling schizophrenia.},
}

@article {pmid41921123,
year = {2026},
author = {Bukhbinder, AS and Ling, Y and Jhin, L and He, E and Harris, K and Rodriguez, M and Thomas, J and Cruz, G and Phelps, K and Kim, Y and Chen, L and Jiang, X and Schulz, PE},
title = {Risk of Alzheimer Dementia After High-Dose vs Standard-Dose Influenza Vaccination.},
journal = {Neurology},
volume = {106},
number = {8},
pages = {e214782},
doi = {10.1212/WNL.0000000000214782},
pmid = {41921123},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/epidemiology/prevention & control ; *Influenza Vaccines/administration & dosage ; Aged ; Female ; Male ; Retrospective Studies ; Aged, 80 and over ; *Vaccination ; Influenza, Human/prevention & control ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunizations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesized that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.

METHODS: This retrospective cohort study analyzed data spanning 2014-2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic or pharmacotherapeutic indicators of cognitive impairment. Vaccinations were identified by name and Current Procedural Terminology codes. Participants were followed for up to 3 years postvaccination. Incident AD was defined using International Classification of Diseases codes and AD medication dispenses (anticholinesterase inhibitors, memantine). We emulated a target trial using sequential nested trials to align eligibility, treatment assignment, and time-zero with vaccination dates, preventing immortal time bias. Inverse probability weighting adjusted for measured confounding, emulated randomization, and mitigated selection bias. Effects were estimated as risk difference, number needed to treat (NNT), risk ratio; 95% CIs were obtained via bootstrapping. Secondary analyses examined potential effect modifiers such as sex.

RESULTS: The H-IIV group included 120,775 unique participants (185,183 person-trials; mean age 74.4 years, SD 5.5; 57.3% female), and the S-IIV group included 44,022 participants (53,918 person-trials; mean age 73.0, SD 6.1; 56.4% female). H-IIV was associated with significantly lower AD risk during months 1-25 postvaccination (minimum NNT = 185.2 at 25 months). After sex stratification, risk reduction persisted longer among women (months 1-13, minimum NNT = 416.7) than men (months 17-24, significant only in intention-to-treat analysis, minimum NNT = 232.6).

DISCUSSION: High-dose influenza vaccination is associated with reduced AD risk compared with standard-dose vaccination in adults ≥65 years, with a stronger effect among women. Significant study limitations included duration of follow-up (≤3 years) and lack of sociodemographic, lifestyle, biomarker, and mortality data. Further research is needed to clarify whether the observed difference reflects protection against influenza infection or non-infection-related mechanisms.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that treatment with H-IIV vs S-IIV was associated with decreased incident dementia in individuals ≥65 years of age captured in this US health care claims database.},
}

Humans
*Alzheimer Disease/epidemiology/prevention & control
*Influenza Vaccines/administration & dosage
Aged
Female
Male
Retrospective Studies
Aged, 80 and over
*Vaccination
Influenza, Human/prevention & control
Cohort Studies

@article {pmid41921847,
year = {2026},
author = {Dong, YR and Wang, JR and Yang, Y and Chen, QZ and Jiang, YQ and Yang, X and Zhou, MC and Cao, SP and Zeng, SX and Zang, CX and Li, FF and Bao, XQ and Zhang, D},
title = {Unveiling the UFMylation Pathway: Implications in neurodegenerative diseases.},
journal = {Journal of molecular biology},
volume = {},
number = {},
pages = {169772},
doi = {10.1016/j.jmb.2026.169772},
pmid = {41921847},
issn = {1089-8638},
abstract = {UFMylation is a recently characterized post-translational modification (PTM) system that conjugates Ubiquitin-Fold Modifier 1 (UFM1) to target proteins via a dedicated enzymatic cascade. This modification system regulates critical cellular processes by controlling protein subcellular localization, modulating protein-protein interactions, and coordinating with ubiquitination to regulate protein stability. Emerging evidence highlights UFMylation as a critical modifier of pathological proteins, including tau and α-synuclein, while impaired UFMylation pathways are observed in the brains of individuals with neurodegenerative disorders. In this review, we summarize the current role and mechanism of UFMylation in the pathogenesis of neurodegenerative diseases, offering the first comprehensive framework for targeting UFMylation in the treatment of neurodegenerative diseases.},
}